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Vladimir V Kalinichenko - One of the best experts on this subject based on the ideXlab platform.
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FOXM1 stimulates progression of lung adenomas into mucinous adenocarcinomas.
2017Co-Authors: David Milewski, Vladimir Ustiyan, Vladimir V Kalinichenko, David Balli, Hendrik Dienemann, Arne Warth, Kai Breuhahn, Jeffrey A. Whitsett, Tanya V KalinAbstract:Schematic drawing shows that FOXF1 induces expression of cell-cycle regulatory and mucinous genes, including Agr2, causing increased tumor cell proliferation and mucinous phenotype. FOXM1 directly activates transcription of Agr2. Both FOXM1 and AGR2 are critical for PIMA growth, invasion and progression of lung adenomas into aggressive mucinous adenocarcinomas.
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SPDEF represses the FOXM1 promoter.
2014Co-Authors: Xin-hua Cheng, Vladimir Ustiyan, Vladimir V Kalinichenko, Jeffrey A. Whitsett, Anusha Sridharan, Markaisa Black, Logan Fulford, Mario Medvedovic, Tanya V KalinAbstract:A. Schematic drawing of the mouse FOXM1 promoter shows the presence of an evolutionary conserved FOXM1 binding site (black oval) and three SPDEF binding sites (white boxes). B. Schematically shown the luciferase (Luc) reporter constructs: Luc I, includes the −3.7 Kb FOXM1 promoter region; Luc II-IV, include one of its deletion mutants; Luc V, includes a construct with mutations in FOXM1 site; Luc VI, includes a construct with mutations in SPDEF site. TRAMP C2 cells were transfected with CMV-FOXM1b or CMV-SPDEF expression vectors and one of the FOXM1 promoter LUC plasmids. CMV-empty plasmid was used as a control. Dual LUC assays were used to determine LUC activity. Transcriptional induction is shown as a fold change relative to CMV-empty vector (± SD). A p value
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the transcription factor foxf1 binds to serum response factor and myocardin to regulate gene transcription in visceral smooth muscle cells
Journal of Biological Chemistry, 2013Co-Authors: April M Hoggatt, Vladimir Ustiyan, Vladimir V Kalinichenko, Tanya V Kalin, Paul B. HerringAbstract:Smooth muscle cells (SMCs) modulate their phenotype from a quiescent contractile state to a dedifferentiated, proliferative and migratory state during the pathogenesis of many diseases, including intestinal pseudoobstruction. Understanding how smooth muscle gene expression is regulated in these different phenotypic states is critical for unraveling the pathogenesis of these diseases. In the current study we examined the specific roles of Foxf1 in visceral SMC differentiation. Data show that Foxf1 is specifically required for expression of several contractile and regulatory proteins such as telokin, smooth muscle γ-actin, and Cav1.2b in visceral SMCs. Mechanistically, Foxf1 directly binds to and activates the telokin promoter. Foxf1 also directly binds to serum response factor (SRF) and myocardin-related transcription factors (MRTFs). Unlike Foxo4 and Foxq1, which bind to MRTFs and block their interaction with SRF, Foxf1 acts synergistically with these proteins to regulate telokin expression. Knock-out of Foxf1 specifically in SMCs results in neonatal lethality, with mice exhibiting GI tract abnormalities. Mice heterozygous for Foxf1 in SMC exhibited impaired colonic contractility and decreased expression of contractile proteins. These studies together with previous studies, suggest that different forkhead proteins can regulate gene expression in SMCs through modulating the activity of the SRF-myocardin axis to either promote or inhibit differentiation and proliferation thereby altering gastrointestinal contractility and development.
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foxo1 and FOXM1 transcription factors have antagonistic functions in neonatal cardiomyocyte cell cycle withdrawal and igf1 gene regulation
Circulation Research, 2013Co-Authors: Arunima Sengupta, Vladimir V Kalinichenko, Katherine E YutzeyAbstract:Rationale: In the mammalian heart, cardiomyocytes withdraw from the cell cycle and initiate hypertrophic growth soon after birth, but the transcriptional regulatory mechanisms that control these neonatal transitions are not well-defined. Objective: Forkhead family transcription factors have been implicated as positive (forkhead box [Fox] transcription factor M1) and negative (FoxO1 and FoxO3) regulators of cardiomyocyte proliferation prenatally, but their regulatory interactions and functions in neonatal cell-cycle withdrawal have not been reported previously. Potential regulators of Fox activity, including the metabolic indicator AMP-activated protein kinase (AMPK), and Fox transcriptional targets ( p21 , p27 , insulin-like growth factor 1 [ IGF1 ]) also were examined. Methods and Results: In cultured neonatal rat cardiomyocytes, AMPK activates FoxOs, and AMPK inhibition is sufficient to induce cell proliferation. In vivo, combined loss of FoxO1 and FoxO3 specifically in cardiomyocytes leads to delayed cell-cycle withdrawal and increased expression of IGF1 and FOXM1 . Conversely, cardiomyocyte-specific loss of FOXM1 results in decreased neonatal cardiomyocyte cell proliferation, decreased expression of IGF1 , and increased expression of cell-cycle inhibitors p21 and p27 . IGF1 is a direct downstream target of cardiac Fox transcription factors, which is negatively regulated by FoxOs and positively regulated by FOXM1, dependent on AMPK activation status. Conclusions: These data support a regulatory mechanism whereby the balance of FoxO and FOXM1 transcription factors integrates metabolic status, mediated by AMPK, and cell-cycle regulation, through competitive regulation of target genes, including IGF1 , in neonatal cardiomyocytes.
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endothelial cell specific deletion of transcription factor FOXM1 increases urethane induced lung carcinogenesis
Cancer Research, 2011Co-Authors: David Balli, Vladimir V Kalinichenko, Yufang Zhang, Jonathan Snyder, Tanya V KalinAbstract:Vascular endothelial cells provide essential support to the tumor microenvironment, but little is known about the transcriptional control of endothelial functions during tumorigenesis. Here we define a critical role for the Forkhead transcription factor FOXM1 in modulating the development of tumor-associated endothelial cells. Pulmonary tumorigenesis induced by urethane administration was compared in mice genetically deleted for FOXM1 in endothelial cells (enFOXM1(-/-) mice). Notably, lung tumor number and size were increased in enFOXM1(-/-) mice. Increased tumorigenesis was associated with increased proliferation of tumor cells and increased expression of c-Myc and cyclin D1. Furthermore, perivascular infiltration by inflammatory cells was elevated and inflammatory cells in BAL fluid were increased. Expression of Flk-1 (vascular endothelial growth factor receptor 2) and FoxF1, known regulators of pulmonary inflammation, was decreased in enFOXM1(-/-) mice. siRNA-mediated knockdown of FOXM1 in endothelial cells reduced Flk-1 and FoxF1 expression, which was driven by direct transcriptional induction by FOXM1 as target genes. Endothelial specific deletion of FOXM1 in vivo or in vitro also decreased expression of Sfrp1 (secreted frizzled-related protein 1), a known inhibitor of canonical Wnt signaling, in a manner that was associated with increased Wnt signaling. Taken together, our results suggest that endothelial-specific expression of FOXM1 limits lung inflammation and canonical Wnt signaling in lung epithelial cells, thereby restricting lung tumorigenesis.
Adam R. Karpf - One of the best experts on this subject based on the ideXlab platform.
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FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer
'MDPI AG', 2021Co-Authors: Cassie Liu, Carter J Barger, Adam R. KarpfAbstract:Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment
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Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer
MDPI AG, 2019Co-Authors: Carter J Barger, Connor Branick, Linda Chee, Adam R. KarpfAbstract:FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer
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abstract b36 FOXM1 induces dna replication stress and its bidirectional gene partner rhno1 participates in the dna replication stress response in high grade serous ovarian cancer
Clinical Cancer Research, 2018Co-Authors: Carter J Barger, Connor Branick, Linda Chee, Kunle Odunsi, Ronny Drapkin, Adam R. KarpfAbstract:Purpose: FOXM1 is located at 12p13.33, which shows copy number gains in the majority of high-grade serous ovarian cancer (HGSC) cases. The 12p13.33 amplicon contains 33 genes, some of which may cooperate with FOXM1 to exert oncogenic function. Although FOXM1 overexpression is associated with genomic instability in cancer, whether FOXM1 contributes directly to this phenotype is unclear. We hypothesized that FOXM1 induces DNA replication stress (DRS), resulting in ATR-CHK1 activation. Intriguingly, we noted that RHNO1, a component of the 9-1-1 complex required for ATR-CHK1 activation, is contained within the 12p13.33 amplicon and is arranged in a head-to-head orientation with FOXM1. Here, we characterized the FOXM1/RHNO1 bidirectional promoter, FOXM1/RHNO1 expression, and determined the role of FOXM1/RHNO1 in DRS, the DRS response, and clonogenic growth of HGSC cells. Methods: We used reporter assays to characterize the FOXM1/RHNO1 bidirectional promoter and FOXM1 transcriptional activity. We analyzed copy number, mRNA, and protein expression datasets in TCGA, CCLE, and GTEX. We measured FOXM1/RHNO1 expression in HGSC cell lines and tumors. We overexpressed FOXM1 in human immortalized fallopian tube epithelial (FTE) cells to determine its contribution to DRS and DNA damage. We knocked down RHNO1 in HGSC cells to determine its contribution to the DRS response and clonogenic growth. We performed Western blot analyses to measure markers of DRS and DNA damage. We characterized FOXM1-induced DNA damage at single-cell resolution using Comet assays and flow cytometry measurement of γ-H2AX. Results: FOXM1/RHNO1 showed copy number gains or amplifications in 58% of TCGA HGSC tumors, and FOXM1/RHNO1 mRNA expression significantly correlated in TCGA HGSC tumors, CCLE HGSC lines, and GTEX normal tissues. The FOXM1/RHNO1 bidirectional promoter showed balanced activity in each direction in FTE and HGSC cells, and bidirectional promoter activity correlated with endogenous mRNA expression. TCGA HGSC data indicated that FOXM1 expression associates with markers of DNA replication, global copy number alterations, and CHK1-Ser345-P, a canonical marker of DRS. In agreement, FOXM1 overexpression in FTE cells induced phosphorylation of ATR-Thr1989, CHK1-Ser317/345, H2AX-Ser139, and the proportion of DNA in Comet tails. In contrast, a DNA-binding domain mutant of FOXM1 did not induce DRS or DNA damage. RHNO1 knockdown attenuated CHK1-Ser345-P in response to DRS and RHNO1 shRNA knockdown or CRISPR-Cas9 knockout severely reduced HGSC cell clonogenic growth. Importantly, the effects of RHNO1 disruption were rescued by WT RHNO1 expression, but not by a RHNO1 mutant defective for interaction with the 9-1-1 complex. Conclusion: Our data reveal that FOXM1/RHNO1 share a bidirectional promoter and that this may account for their frequent coexpression in HGSC. FOXM1 induces DRS, and this is dependent on its ability to bind DNA. Conversely, RHNO1 contributes to ATR-CHK1 signaling and promotes the clonogenic growth of HGSC cells. We hypothesize that balanced FOXM1/RHNO1 expression promotes HGSC development and progression. Ongoing studies are characterizing the impact of FOXM1/RHNO1 on DRS and genomic instability in model systems. Finally, our data suggest that the ATR-CHK1 pathway is a synthetic lethal vulnerability in HGSC tumors that overexpress FOXM1. Citation Format: Carter J. Barger, Linda Chee, Connor Branick, Kunle Odunsi, Ronny Drapkin, Adam R. Karpf. FOXM1 induces DNA replication stress, and its bidirectional gene partner RHNO1 participates in the DNA replication stress response, in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B36.
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abstract mip 044 FOXM1 induced replication stress is mitigated by its bidirectional gene partner rhno1 in high grade serous ovarian cancer
Clinical Cancer Research, 2017Co-Authors: Carter J Barger, Linda Chee, Kunle Odunsi, Ronny Drapkin, Adam R. KarpfAbstract:PURPOSE : FOXM1 is located at 12p13.33, a significantly amplified locus in high-grade serous ovarian cancer (HGSC). The 12p13.33 amplicon contains ~33 genes, which may cooperate with FOXM1 to exert oncogenic function. Although FOXM1 expression is associated with cancer genomic instability, it is unclear whether FOXM1 causes this phenotype and, if so, by what mechanism. We hypothesized that FOXM1 induces replication stress, which is the slowing or stalling of replication forks. We further noted that RHNO1 , a component of the 9-1-1 complex required for ATR-CHK1 signaling, is contained within the 12p13.33 amplicon, and arranged in a head-to-head orientation with FOXM1 . Here, we characterized the FOXM1-RHNO1 bidirectional promoter, FOXM1 and RHNO1 expression patterns in HGSC, and determined the relationship between FOXM1 and RHNO1 in replication stress. METHODS: We used 59 RACE and a luciferase reporter construct to characterize the FOXM1-RHNO1 bidirectional promoter. We analyzed copy number, mRNA and protein expression datasets in TCGA HGSC and additional TCGA cancers. We measured FOXM1 and RHNO1 expression in HGSC cell lines and primary HGSC tissues. We overexpressed FOXM1 in human immortalized fallopian tube epithelial (FTE) cells to determine its contribution to replication stress. We used RHNO1 knockdown to dissect its functional contribution to ATR-CHK1 signaling in HGSC cells. RESULTS: FOXM1 and RHNO1 were co-amplified in ~12% of HGSC and their mRNA expressions were highly correlated. The FOXM1-RHNO1 bidirectional promoter showed similar activity in each direction in HGSC cells, and correlated with mRNA expression. Analysis of TCGA HGSC data revealed that FOXM1 associates with markers of DNA replication and CHK1-Ser345 phosphorylation, a canonical marker of replication stress. FOXM1 overexpression in immortalized FTE cells induced CHK1-Ser345 phosphorylation. RHNO1 knockdown attenuated CHK1-Ser345 phosphorylation in response to replication stress, and, importantly, reduced clonogenic growth in FOXM1 overexpressing HGSC cells. CONCLUSIONS: Our data reveal that FOXM1 and RHNO1 share a bidirectional promoter resulting in their frequent co-expression. FOXM1 induces replication stress whereas RHNO1 is necessary for efficient ATR-CHK1 signaling. We hypothesize that balanced FOXM1 and RHNO1 expression promotes HGSC development and progression. Ongoing studies are characterizing the impact of FOXM1 and RHNO1 on replication stress and genomic instability. Finally, our findings suggest ATR-CHK1 signaling as a potential therapeutic vulnerability in FOXM1 activated HGSC. Citation Format: Carter J Barger, Linda Chee, Ronny Drapkin, Kunle Odunsi, Adam R. Karpf. FOXM1 INDUCED REPLICATION STRESS IS MITIGATED BY ITS BIDIRECTIONAL GENE PARTNER, RHNO1, IN HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-044.
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genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression
Oncotarget, 2015Co-Authors: Carter J Barger, Wa Zhang, Joanna Hillman, Aimee Stablewski, Michael J Higgins, Barbara C Vanderhyden, Kunle Odunsi, Adam R. KarpfAbstract:The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSE-SV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models.
Robert H Costa - One of the best experts on this subject based on the ideXlab platform.
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FOXM1 a critical regulator of oxidative stress during oncogenesis
The EMBO Journal, 2009Co-Authors: Hyun Jung Park, Robert H Costa, Angela L Tyner, Janai R Carr, Zebin Wang, Veronique Nogueira, Nissim Hay, Lester F Lau, Pradip RaychaudhuriAbstract:The transcription factor FOXM1 is over-expressed in most human malignancies. Although it is evident that FOXM1 has critical functions in tumour development and progression, the mechanisms by which FOXM1 participates in those processes are not understood. Here, we describe an essential role of FOXM1 in the regulation of oxidative stress that contributes to malignant transformation and tumour cell survival. We identify a negative feedback loop involving FOXM1 that regulates reactive oxygen species (ROS) in proliferating cells. We show that induction of FOXM1 by oncogenic Ras requires ROS. Elevated FOXM1, in turn, downregulates ROS levels by stimulating expression of ROS scavenger genes, such as MnSOD, catalase and PRDX3. FOXM1 depletion sensitizes cells to oxidative stress and increases oncogene-induced premature senescence. Moreover, tumour cells expressing activated AKT1 are 'addicted' to FOXM1, as they require continuous presence of FOXM1 for survival. Together, our results identify FOXM1 as a key regulator of ROS in dividing cells, and provide insights into the mechanism how tumour cells use FOXM1 to control oxidative stress to escape premature senescence and apoptosis.
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FOXM1 regulates growth factor induced expression of kinase interacting stathmin kis to promote cell cycle progression
Journal of Biological Chemistry, 2008Co-Authors: Vladimir Petrovic, Robert H Costa, Pradip Raychaudhuri, Angela L TynerAbstract:Abstract The Forkhead box M1 (FOXM1) transcription factor is essential for cell cycle progression and mitosis. FOXM1 regulates expression of Skp2 and Cks1, subunits of the SCF ubiquitin ligase complex, which ubiquitinates p27Kip1 and targets it for degradation. Kinase-interacting stathmin (KIS) is a growth factor-dependent nuclear kinase that regulates cell cycle progression by phosphorylating p27Kip1 to promote its nuclear export. Here we present an additional mechanism of FOXM1-mediated regulation of p27Kip1 and provide evidence that FOXM1 regulates growth factor-induced expression of KIS. In cells harboring FOXM1 deletion or expressing FOXM1-short interfering RNA, the expression of KIS is impaired, leading to an accumulation of p27Kip1 in the nucleus. Furthermore, we show that KIS is a direct transcriptional target of FOXM1. Thus FOXM1 promotes cell cycle progression by down-regulating p27Kip1 through multiple mechanisms.
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the forkhead box m1 transcription factor contributes to the development and growth of mouse colorectal cancer
Gastroenterology, 2007Co-Authors: Yuichi Yoshida, Helena M Yoder, Ching I Wang, Nicholas O Davidson, Robert H CostaAbstract:Background & Aims: In this study, we used Forkhead Box m1b (FOXM1b) transgenic mice and conditional FOXM1 knock-out mice to examine the role of FOXM1 in colon cancer development and proliferation. Methods: To induce mouse colorectal cancer, we used a single intraperitoneal injection of azoxymethane (AOM) followed by three 1-week cycles of 2.5% dextran sodium sulfate (DSS) water, each cycle separated by 2 weeks. For these colon tumor studies, we used either Rosa26-FOXM1b transgenic mice that ubiquitously expressed the human FOXM1b complementary DNA or mice in which the FOXM1 fl/fl targeted allele was deleted in colonic epithelial cells using the gut-specific Villin-Cre recombinase transgene (Villin-Cre). Colorectal tumor number and bromodeoxyuridine labeling were determined in Rosa26-FOXM1b mice, Villin-Cre FOXM1-/-, mice and wild-type mice after 12 weeks of AOM/DDS exposure. We also used FOXM1 small interfering RNA–depleted human DLD1 and mouse CT26 colon cancer cell lines to examine DNA replication and anchorage-independent growth. Results: After 12 weeks of treatment with AOM/DSS, Rosa26 FOXM1b transgenic mice showed an increase in the number and size of colorectal tumors compared with wild-type mice. Likewise, a significant reduction in the development and growth of colorectal tumors was found in Villin-Cre FOXM1-/- mice compared with FOXM1 fl/fl mice after AOM/DSS treatment, which was associated with decreased expression of cyclin A2, cyclin B1, survivin, and T-cell factor 4 genes. Moreover, FOXM1-depleted colon cancer cell lines showed reduced DNA replication and anchorage-independent growth. Conclusions: These studies suggest that FOXM1 is critical for the proliferation and growth of colorectal cancer.
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a cell penetrating arf peptide inhibitor of FOXM1 in mouse hepatocellular carcinoma treatment
Journal of Clinical Investigation, 2007Co-Authors: Galina A Gusarova, Vladimir V Kalinichenko, Vladimir Petrovic, Iching Wang, Timothy Ackerson, Michael L Major, Robert H CostaAbstract:Theforkhead box m1�(FOXM1) transcriptionfactorisessentialforinitiationofcarcinogen-inducedlivertumors;� however,�whetherFOXM1�constitutesatherapeutictargetforlivercancertreatmentremainsunknown.�Inthis� study,�weuseddiethylnitrosamine/phenobarbitaltreatmenttoinducehepatocellularcarcinomas�(HCCs)� ineitherWTmiceorArf -/- �Rosa26-FOXM1bTgmice,�inwhichforkheadboxM1b�(FOXM1b)�isoverexpressed� andalternativereadingframe�(ARF)�inhibitionofFOXM1�transcriptionalactivityiseliminated.�Tophar- macologicallyreduceFOXM1 activityin HCCs,�wesubjectedtheseHCC-bearingmicetodailyinjectionsofa� cell-penetratingARF26-44�peptideinhibitorofFOXM1�function.�After�4�weeksofthistreatment,�HCCregions� displayedreducedtumorcellproliferationandangiogenesisandasignificantincreaseinapoptosiswithin� theHCCregionbutnotintheadjacentnormallivertissue.�ARFpeptidetreatmentalsoinducedapoptosisof� severaldistincthumanhepatomacelllines,�whichcorrelatedwithreducedproteinlevelsofthemitoticregula- torygenesencodingpolo-likekinase�1,�auroraBkinase,�andsurvivin,�allofwhicharetranscriptionaltargets� ofFOXM1�thatarehighlyexpressedincancercellsandfunctiontopreventapoptosis.�Thesestudiesindicate� thatARFpeptidetreatmentisaneffectivetherapeuticapproachtolimitproliferationandinduceapoptosis� oflivercancercellsinvivo.
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the forkhead box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer
Cancer Research, 2006Co-Authors: Ilman Kim, Tanya V Kalin, Galina A Gusarova, Iching Wang, Helena M Yoder, Timothy Ackerson, Sneha Ramakrishna, Maria Tretiakova, Michael L Major, Robert H CostaAbstract:The proliferation-specific Forkhead Box m1 (FOXM1 or FOXM1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) regulates expression of cell cycle genes essential for progression into DNA replication and mitosis. Expression of FOXM1 is found in a variety of distinct human cancers including hepatocellular carcinomas, intrahepatic cholangiocarcinomas, basal cell carcinomas, ductal breast carcinomas, and anaplastic astrocytomas and glioblastomas. In this study, we show that human FOXM1 protein is abundantly expressed in highly proliferative human non–small cell lung cancers (NSCLC) as well as in mouse lung tumors induced by urethane. To determine the role of FOXM1 during the development of mouse lung tumors, we used IFN-inducible Mx-Cre recombinase transgene to delete mouse FOXM1 fl/fl–targeted allele before inducing lung tumors with urethane. We show that Mx-Cre FOXM1 −/− mice exhibit diminished proliferation of lung tumor cells causing a significant reduction in number and size of lung adenomas. Transient transfection experiments with A549 lung adenocarcinoma cells show that depletion of FOXM1 levels by short interfering RNA caused diminished DNA replication and mitosis and reduced anchorage-independent growth of cell colonies on soft agar. FOXM1-depleted A549 cells exhibit reduced expression of cell cycle–promoting cyclin A2 and cyclin B1 genes. These data show that FOXM1 stimulates the proliferation of tumor cells during progression of NSCLC. (Cancer Res 2006; 66(4): 2153-61)
Carter J Barger - One of the best experts on this subject based on the ideXlab platform.
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FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer
'MDPI AG', 2021Co-Authors: Cassie Liu, Carter J Barger, Adam R. KarpfAbstract:Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment
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Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer
MDPI AG, 2019Co-Authors: Carter J Barger, Connor Branick, Linda Chee, Adam R. KarpfAbstract:FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer
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abstract b36 FOXM1 induces dna replication stress and its bidirectional gene partner rhno1 participates in the dna replication stress response in high grade serous ovarian cancer
Clinical Cancer Research, 2018Co-Authors: Carter J Barger, Connor Branick, Linda Chee, Kunle Odunsi, Ronny Drapkin, Adam R. KarpfAbstract:Purpose: FOXM1 is located at 12p13.33, which shows copy number gains in the majority of high-grade serous ovarian cancer (HGSC) cases. The 12p13.33 amplicon contains 33 genes, some of which may cooperate with FOXM1 to exert oncogenic function. Although FOXM1 overexpression is associated with genomic instability in cancer, whether FOXM1 contributes directly to this phenotype is unclear. We hypothesized that FOXM1 induces DNA replication stress (DRS), resulting in ATR-CHK1 activation. Intriguingly, we noted that RHNO1, a component of the 9-1-1 complex required for ATR-CHK1 activation, is contained within the 12p13.33 amplicon and is arranged in a head-to-head orientation with FOXM1. Here, we characterized the FOXM1/RHNO1 bidirectional promoter, FOXM1/RHNO1 expression, and determined the role of FOXM1/RHNO1 in DRS, the DRS response, and clonogenic growth of HGSC cells. Methods: We used reporter assays to characterize the FOXM1/RHNO1 bidirectional promoter and FOXM1 transcriptional activity. We analyzed copy number, mRNA, and protein expression datasets in TCGA, CCLE, and GTEX. We measured FOXM1/RHNO1 expression in HGSC cell lines and tumors. We overexpressed FOXM1 in human immortalized fallopian tube epithelial (FTE) cells to determine its contribution to DRS and DNA damage. We knocked down RHNO1 in HGSC cells to determine its contribution to the DRS response and clonogenic growth. We performed Western blot analyses to measure markers of DRS and DNA damage. We characterized FOXM1-induced DNA damage at single-cell resolution using Comet assays and flow cytometry measurement of γ-H2AX. Results: FOXM1/RHNO1 showed copy number gains or amplifications in 58% of TCGA HGSC tumors, and FOXM1/RHNO1 mRNA expression significantly correlated in TCGA HGSC tumors, CCLE HGSC lines, and GTEX normal tissues. The FOXM1/RHNO1 bidirectional promoter showed balanced activity in each direction in FTE and HGSC cells, and bidirectional promoter activity correlated with endogenous mRNA expression. TCGA HGSC data indicated that FOXM1 expression associates with markers of DNA replication, global copy number alterations, and CHK1-Ser345-P, a canonical marker of DRS. In agreement, FOXM1 overexpression in FTE cells induced phosphorylation of ATR-Thr1989, CHK1-Ser317/345, H2AX-Ser139, and the proportion of DNA in Comet tails. In contrast, a DNA-binding domain mutant of FOXM1 did not induce DRS or DNA damage. RHNO1 knockdown attenuated CHK1-Ser345-P in response to DRS and RHNO1 shRNA knockdown or CRISPR-Cas9 knockout severely reduced HGSC cell clonogenic growth. Importantly, the effects of RHNO1 disruption were rescued by WT RHNO1 expression, but not by a RHNO1 mutant defective for interaction with the 9-1-1 complex. Conclusion: Our data reveal that FOXM1/RHNO1 share a bidirectional promoter and that this may account for their frequent coexpression in HGSC. FOXM1 induces DRS, and this is dependent on its ability to bind DNA. Conversely, RHNO1 contributes to ATR-CHK1 signaling and promotes the clonogenic growth of HGSC cells. We hypothesize that balanced FOXM1/RHNO1 expression promotes HGSC development and progression. Ongoing studies are characterizing the impact of FOXM1/RHNO1 on DRS and genomic instability in model systems. Finally, our data suggest that the ATR-CHK1 pathway is a synthetic lethal vulnerability in HGSC tumors that overexpress FOXM1. Citation Format: Carter J. Barger, Linda Chee, Connor Branick, Kunle Odunsi, Ronny Drapkin, Adam R. Karpf. FOXM1 induces DNA replication stress, and its bidirectional gene partner RHNO1 participates in the DNA replication stress response, in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B36.
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abstract mip 044 FOXM1 induced replication stress is mitigated by its bidirectional gene partner rhno1 in high grade serous ovarian cancer
Clinical Cancer Research, 2017Co-Authors: Carter J Barger, Linda Chee, Kunle Odunsi, Ronny Drapkin, Adam R. KarpfAbstract:PURPOSE : FOXM1 is located at 12p13.33, a significantly amplified locus in high-grade serous ovarian cancer (HGSC). The 12p13.33 amplicon contains ~33 genes, which may cooperate with FOXM1 to exert oncogenic function. Although FOXM1 expression is associated with cancer genomic instability, it is unclear whether FOXM1 causes this phenotype and, if so, by what mechanism. We hypothesized that FOXM1 induces replication stress, which is the slowing or stalling of replication forks. We further noted that RHNO1 , a component of the 9-1-1 complex required for ATR-CHK1 signaling, is contained within the 12p13.33 amplicon, and arranged in a head-to-head orientation with FOXM1 . Here, we characterized the FOXM1-RHNO1 bidirectional promoter, FOXM1 and RHNO1 expression patterns in HGSC, and determined the relationship between FOXM1 and RHNO1 in replication stress. METHODS: We used 59 RACE and a luciferase reporter construct to characterize the FOXM1-RHNO1 bidirectional promoter. We analyzed copy number, mRNA and protein expression datasets in TCGA HGSC and additional TCGA cancers. We measured FOXM1 and RHNO1 expression in HGSC cell lines and primary HGSC tissues. We overexpressed FOXM1 in human immortalized fallopian tube epithelial (FTE) cells to determine its contribution to replication stress. We used RHNO1 knockdown to dissect its functional contribution to ATR-CHK1 signaling in HGSC cells. RESULTS: FOXM1 and RHNO1 were co-amplified in ~12% of HGSC and their mRNA expressions were highly correlated. The FOXM1-RHNO1 bidirectional promoter showed similar activity in each direction in HGSC cells, and correlated with mRNA expression. Analysis of TCGA HGSC data revealed that FOXM1 associates with markers of DNA replication and CHK1-Ser345 phosphorylation, a canonical marker of replication stress. FOXM1 overexpression in immortalized FTE cells induced CHK1-Ser345 phosphorylation. RHNO1 knockdown attenuated CHK1-Ser345 phosphorylation in response to replication stress, and, importantly, reduced clonogenic growth in FOXM1 overexpressing HGSC cells. CONCLUSIONS: Our data reveal that FOXM1 and RHNO1 share a bidirectional promoter resulting in their frequent co-expression. FOXM1 induces replication stress whereas RHNO1 is necessary for efficient ATR-CHK1 signaling. We hypothesize that balanced FOXM1 and RHNO1 expression promotes HGSC development and progression. Ongoing studies are characterizing the impact of FOXM1 and RHNO1 on replication stress and genomic instability. Finally, our findings suggest ATR-CHK1 signaling as a potential therapeutic vulnerability in FOXM1 activated HGSC. Citation Format: Carter J Barger, Linda Chee, Ronny Drapkin, Kunle Odunsi, Adam R. Karpf. FOXM1 INDUCED REPLICATION STRESS IS MITIGATED BY ITS BIDIRECTIONAL GENE PARTNER, RHNO1, IN HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-044.
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genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression
Oncotarget, 2015Co-Authors: Carter J Barger, Wa Zhang, Joanna Hillman, Aimee Stablewski, Michael J Higgins, Barbara C Vanderhyden, Kunle Odunsi, Adam R. KarpfAbstract:The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSE-SV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models.
Kunle Odunsi - One of the best experts on this subject based on the ideXlab platform.
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abstract b36 FOXM1 induces dna replication stress and its bidirectional gene partner rhno1 participates in the dna replication stress response in high grade serous ovarian cancer
Clinical Cancer Research, 2018Co-Authors: Carter J Barger, Connor Branick, Linda Chee, Kunle Odunsi, Ronny Drapkin, Adam R. KarpfAbstract:Purpose: FOXM1 is located at 12p13.33, which shows copy number gains in the majority of high-grade serous ovarian cancer (HGSC) cases. The 12p13.33 amplicon contains 33 genes, some of which may cooperate with FOXM1 to exert oncogenic function. Although FOXM1 overexpression is associated with genomic instability in cancer, whether FOXM1 contributes directly to this phenotype is unclear. We hypothesized that FOXM1 induces DNA replication stress (DRS), resulting in ATR-CHK1 activation. Intriguingly, we noted that RHNO1, a component of the 9-1-1 complex required for ATR-CHK1 activation, is contained within the 12p13.33 amplicon and is arranged in a head-to-head orientation with FOXM1. Here, we characterized the FOXM1/RHNO1 bidirectional promoter, FOXM1/RHNO1 expression, and determined the role of FOXM1/RHNO1 in DRS, the DRS response, and clonogenic growth of HGSC cells. Methods: We used reporter assays to characterize the FOXM1/RHNO1 bidirectional promoter and FOXM1 transcriptional activity. We analyzed copy number, mRNA, and protein expression datasets in TCGA, CCLE, and GTEX. We measured FOXM1/RHNO1 expression in HGSC cell lines and tumors. We overexpressed FOXM1 in human immortalized fallopian tube epithelial (FTE) cells to determine its contribution to DRS and DNA damage. We knocked down RHNO1 in HGSC cells to determine its contribution to the DRS response and clonogenic growth. We performed Western blot analyses to measure markers of DRS and DNA damage. We characterized FOXM1-induced DNA damage at single-cell resolution using Comet assays and flow cytometry measurement of γ-H2AX. Results: FOXM1/RHNO1 showed copy number gains or amplifications in 58% of TCGA HGSC tumors, and FOXM1/RHNO1 mRNA expression significantly correlated in TCGA HGSC tumors, CCLE HGSC lines, and GTEX normal tissues. The FOXM1/RHNO1 bidirectional promoter showed balanced activity in each direction in FTE and HGSC cells, and bidirectional promoter activity correlated with endogenous mRNA expression. TCGA HGSC data indicated that FOXM1 expression associates with markers of DNA replication, global copy number alterations, and CHK1-Ser345-P, a canonical marker of DRS. In agreement, FOXM1 overexpression in FTE cells induced phosphorylation of ATR-Thr1989, CHK1-Ser317/345, H2AX-Ser139, and the proportion of DNA in Comet tails. In contrast, a DNA-binding domain mutant of FOXM1 did not induce DRS or DNA damage. RHNO1 knockdown attenuated CHK1-Ser345-P in response to DRS and RHNO1 shRNA knockdown or CRISPR-Cas9 knockout severely reduced HGSC cell clonogenic growth. Importantly, the effects of RHNO1 disruption were rescued by WT RHNO1 expression, but not by a RHNO1 mutant defective for interaction with the 9-1-1 complex. Conclusion: Our data reveal that FOXM1/RHNO1 share a bidirectional promoter and that this may account for their frequent coexpression in HGSC. FOXM1 induces DRS, and this is dependent on its ability to bind DNA. Conversely, RHNO1 contributes to ATR-CHK1 signaling and promotes the clonogenic growth of HGSC cells. We hypothesize that balanced FOXM1/RHNO1 expression promotes HGSC development and progression. Ongoing studies are characterizing the impact of FOXM1/RHNO1 on DRS and genomic instability in model systems. Finally, our data suggest that the ATR-CHK1 pathway is a synthetic lethal vulnerability in HGSC tumors that overexpress FOXM1. Citation Format: Carter J. Barger, Linda Chee, Connor Branick, Kunle Odunsi, Ronny Drapkin, Adam R. Karpf. FOXM1 induces DNA replication stress, and its bidirectional gene partner RHNO1 participates in the DNA replication stress response, in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B36.
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abstract mip 044 FOXM1 induced replication stress is mitigated by its bidirectional gene partner rhno1 in high grade serous ovarian cancer
Clinical Cancer Research, 2017Co-Authors: Carter J Barger, Linda Chee, Kunle Odunsi, Ronny Drapkin, Adam R. KarpfAbstract:PURPOSE : FOXM1 is located at 12p13.33, a significantly amplified locus in high-grade serous ovarian cancer (HGSC). The 12p13.33 amplicon contains ~33 genes, which may cooperate with FOXM1 to exert oncogenic function. Although FOXM1 expression is associated with cancer genomic instability, it is unclear whether FOXM1 causes this phenotype and, if so, by what mechanism. We hypothesized that FOXM1 induces replication stress, which is the slowing or stalling of replication forks. We further noted that RHNO1 , a component of the 9-1-1 complex required for ATR-CHK1 signaling, is contained within the 12p13.33 amplicon, and arranged in a head-to-head orientation with FOXM1 . Here, we characterized the FOXM1-RHNO1 bidirectional promoter, FOXM1 and RHNO1 expression patterns in HGSC, and determined the relationship between FOXM1 and RHNO1 in replication stress. METHODS: We used 59 RACE and a luciferase reporter construct to characterize the FOXM1-RHNO1 bidirectional promoter. We analyzed copy number, mRNA and protein expression datasets in TCGA HGSC and additional TCGA cancers. We measured FOXM1 and RHNO1 expression in HGSC cell lines and primary HGSC tissues. We overexpressed FOXM1 in human immortalized fallopian tube epithelial (FTE) cells to determine its contribution to replication stress. We used RHNO1 knockdown to dissect its functional contribution to ATR-CHK1 signaling in HGSC cells. RESULTS: FOXM1 and RHNO1 were co-amplified in ~12% of HGSC and their mRNA expressions were highly correlated. The FOXM1-RHNO1 bidirectional promoter showed similar activity in each direction in HGSC cells, and correlated with mRNA expression. Analysis of TCGA HGSC data revealed that FOXM1 associates with markers of DNA replication and CHK1-Ser345 phosphorylation, a canonical marker of replication stress. FOXM1 overexpression in immortalized FTE cells induced CHK1-Ser345 phosphorylation. RHNO1 knockdown attenuated CHK1-Ser345 phosphorylation in response to replication stress, and, importantly, reduced clonogenic growth in FOXM1 overexpressing HGSC cells. CONCLUSIONS: Our data reveal that FOXM1 and RHNO1 share a bidirectional promoter resulting in their frequent co-expression. FOXM1 induces replication stress whereas RHNO1 is necessary for efficient ATR-CHK1 signaling. We hypothesize that balanced FOXM1 and RHNO1 expression promotes HGSC development and progression. Ongoing studies are characterizing the impact of FOXM1 and RHNO1 on replication stress and genomic instability. Finally, our findings suggest ATR-CHK1 signaling as a potential therapeutic vulnerability in FOXM1 activated HGSC. Citation Format: Carter J Barger, Linda Chee, Ronny Drapkin, Kunle Odunsi, Adam R. Karpf. FOXM1 INDUCED REPLICATION STRESS IS MITIGATED BY ITS BIDIRECTIONAL GENE PARTNER, RHNO1, IN HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-044.
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genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression
Oncotarget, 2015Co-Authors: Carter J Barger, Wa Zhang, Joanna Hillman, Aimee Stablewski, Michael J Higgins, Barbara C Vanderhyden, Kunle Odunsi, Adam R. KarpfAbstract:The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSE-SV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models.
