The Experts below are selected from a list of 7323 Experts worldwide ranked by ideXlab platform
Zihua Gong - One of the best experts on this subject based on the ideXlab platform.
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ck2 kinase mediated PHF8 phosphorylation controls topbp1 stability to regulate dna replication
Nucleic Acids Research, 2020Co-Authors: Haihua Feng, Zihua Gong, Xiaotian Song, Angkana Thongkum, Fan Zhang, Lihong Lou, Ofer Reizes, Alexandru AlmasanAbstract:ATR functions as a master regulator of the DNA-damage response. ATR activation requires the ATR activator, topoisomerase IIβ-binding protein 1 (TopBP1). However, the underlying mechanism of TopBP1 regulation and how its regulation affects DNA replication remain unknown. Here, we report a specific interaction between TopBP1 and the histone demethylase PHF8. The TopBP1/PHF8 interaction is mediated by the BRCT 7+8 domain of TopBP1 and phosphorylation of PHF8 at Ser854. This interaction is cell-cycle regulated and phosphorylation-dependent. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. Importantly, PHF8 regulates TopBP1 protein level by preventing its ubiquitination and degradation mediated by the E3 ligase UBR5. Interestingly, PHF8pS854 is likely to contribute to regulation of TopBP1 stability and DNA replication checkpoint. Further, both TopBP1 and PHF8 are required for efficient replication fork restart. Together, these data identify PHF8 as a TopBP1-binding protein and provide mechanistic insight into how PHF8 regulates TopBP1 stability to maintain DNA replication.
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phf6 regulates cell cycle progression by suppressing ribosomal rna synthesis
Epigenetics & Chromatin, 2013Co-Authors: Jiadong Wang, Justin W C Leung, Zihua Gong, Lin Feng, Junjie ChenAbstract:Mutation of PHF6, which results in X-linked mental retardation disorder-Borjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with UBF through its PHD1 domain and suppresses rRNA transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by increased level of phosphorylated H2AX (γ-H2AX), indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at rDNA locus in PHF6-deficient cells. This effect could be reversed by knocking-down UBF or over-expressing RNASE1, which removes RNA:DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance and tumor suppression.
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phf6 regulates cell cycle progression by suppressing ribosomal rna synthesis
Journal of Biological Chemistry, 2013Co-Authors: Jiadong Wang, Justin W C Leung, Zihua Gong, Lin Feng, Junjie ChenAbstract:Mutation of PHF6, which results in the X-linked mental retardation disorder Borjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with upstream binding factor (UBF) through its PHD1 domain and suppresses ribosomal RNA (rRNA) transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by an increased level of phosphorylated H2AX, indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at the ribosomal DNA (rDNA) locus in PHF6-deficient cells. This effect could be reversed by knocking down UBF or overexpressing RNASE1, which removes RNA-DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at the rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression.
Junjie Chen - One of the best experts on this subject based on the ideXlab platform.
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phf6 regulates cell cycle progression by suppressing ribosomal rna synthesis
Epigenetics & Chromatin, 2013Co-Authors: Jiadong Wang, Justin W C Leung, Zihua Gong, Lin Feng, Junjie ChenAbstract:Mutation of PHF6, which results in X-linked mental retardation disorder-Borjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with UBF through its PHD1 domain and suppresses rRNA transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by increased level of phosphorylated H2AX (γ-H2AX), indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at rDNA locus in PHF6-deficient cells. This effect could be reversed by knocking-down UBF or over-expressing RNASE1, which removes RNA:DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance and tumor suppression.
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phf6 regulates cell cycle progression by suppressing ribosomal rna synthesis
Journal of Biological Chemistry, 2013Co-Authors: Jiadong Wang, Justin W C Leung, Zihua Gong, Lin Feng, Junjie ChenAbstract:Mutation of PHF6, which results in the X-linked mental retardation disorder Borjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with upstream binding factor (UBF) through its PHD1 domain and suppresses ribosomal RNA (rRNA) transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by an increased level of phosphorylated H2AX, indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at the ribosomal DNA (rDNA) locus in PHF6-deficient cells. This effect could be reversed by knocking down UBF or overexpressing RNASE1, which removes RNA-DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at the rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression.
Huang-tian Yang - One of the best experts on this subject based on the ideXlab platform.
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plant homeo domain finger protein 8 regulates mesodermal and cardiac differentiation of embryonic stem cells through mediating the histone demethylation of pmaip1
Stem Cells, 2016Co-Authors: Yan Tang, Ya-zhen Hong, H. Y. Bai, Charlie Degui Chen, Jing-yu Lang, Kenneth R. Boheler, Huang-tian YangAbstract:Histone demethylases have emerged as key regulators of biological processes. The H3K9me2 demethylase plant homeo domain finger protein 8(PHF8), for example, is involved in neuronal differentiation, but its potential function in the differentiation of embryonic stem cells (ESCs) to cardiomyocytes is poorly understood. Here, we explored the role of PHF8 during mesodermal and cardiac lineage commitment of mouse ESCs (mESCs). Using a PHF8 knockout (ph8(-/Y) ) model, we found that deletion of PHF8 in ESCs did not affect self-renewal, proliferation or early ectodermal/endodermal differentiation, but it did promote the mesodermal lineage commitment with the enhanced cardiomyocyte differentiation. The effects were accompanied by a reduction in apoptosis through a caspase 3-independent pathway during early ESC differentiation, without significant differences between differentiating wide-type (ph8(+/Y) ) and ph8(-/Y) ESCs in cell cycle progression or proliferation. Functionally, PHF8 promoted the loss of a repressive mark H3K9me2 from the transcription start site of a proapoptotic gene pmaip1 and activated its transcription. Furthermore, knockdown of pmaip1 mimicked the phenotype of ph8(-/Y) by showing the decreased apoptosis during early differentiation of ESCs and promoted mesodermal and cardiac commitment, while overexpression of pmaip1 or PHF8 rescued the phenotype of ph8(-/Y) ESCs by increasing the apoptosis and weakening the mesodermal and cardiac differentiation. These results reveal that the histone demethylase PHF8 regulates mesodermal lineage and cell fate decisions in differentiating mESCs through epigenetic control of the gene critical to programmed cell death pathways. Stem Cells 2016;34:1527-1540.
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PHF8 regulates mesodermal and cardiac differentiation of embryonic stem cells through mediating the histone demethylation of pmaip1
Stem cells (Dayton Ohio), 2016Co-Authors: Yan Tang, Ya-zhen Hong, H. Y. Bai, Charlie Degui Chen, Jing-yu Lang, Kenneth R. Boheler, Huang-tian YangAbstract:Histone demethylases have emerged as key regulators of biological processes. The H3K9me2 demethylase plant homeo domain finger protein 8(PHF8), for example, is involved in neuronal differentiation, but its potential function in the differentiation of embryonic stem cells (ESCs) to cardiomyocytes is poorly understood. Here, we explored the role of PHF8 during mesodermal and cardiac lineage commitment of mouse ESCs (mESCs). Using a PHF8 knockout (ph8(-/Y) ) model, we found that deletion of PHF8 in ESCs did not affect self-renewal, proliferation or early ectodermal/endodermal differentiation, but it did promote the mesodermal lineage commitment with the enhanced cardiomyocyte differentiation. The effects were accompanied by a reduction in apoptosis through a caspase 3-independent pathway during early ESC differentiation, without significant differences between differentiating wide-type (ph8(+/Y) ) and ph8(-/Y) ESCs in cell cycle progression or proliferation. Functionally, PHF8 promoted the loss of a repressive mark H3K9me2 from the transcription start site of a proapoptotic gene pmaip1 and activated its transcription. Furthermore, knockdown of pmaip1 mimicked the phenotype of ph8(-/Y) by showing the decreased apoptosis during early differentiation of ESCs and promoted mesodermal and cardiac commitment, while overexpression of pmaip1 or PHF8 rescued the phenotype of ph8(-/Y) ESCs by increasing the apoptosis and weakening the mesodermal and cardiac differentiation. These results reveal that the histone demethylase PHF8 regulates mesodermal lineage and cell fate decisions in differentiating mESCs through epigenetic control of the gene critical to programmed cell death pathways. Stem Cells 2016;34:1527-1540.
Peterson Kariuki Maina - One of the best experts on this subject based on the ideXlab platform.
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contribution of synergism between PHF8 and her2 signalling to breast cancer development and drug resistance
EBioMedicine, 2020Co-Authors: Peng Shao, Qi Liu, Peterson Kariuki Maina, Nicholas Borcherding, Weizhou ZhangAbstract:Abstract Background HER2 plays a critical role in tumourigenesis and is associated with poor prognosis of patients with HER2-positive breast cancers. Although anti-HER2 drugs are beneficial for treating breast cancer, de novo, or acquired resistance often develops. Epigenetic factors are increasingly targeted for therapy; however, such mechanisms that interact with HER2 signalling are poorly understood. Methods RNA sequencing was performed to identify PHF8 targets downstream of HER2 signalling. CHIP-qPCR were used to investigate how PHF8 regulates HER2 transcription. ELISA determined cytokine secretion. Cell-based assay revealed a feed forward loop in HER2 signalling and then evaluated in vivo. Findings We report the synergistic interplay between histone demethylase PHF8 and HER2 signalling. Specifically, PHF8 levels were elevated in HER2-positive breast cancers and upregulated by HER2. PHF8 functioned as a coactivator that regulated the expression of HER2, markers of the HER2-driven epithelial-to-mesenchymal transition and cytokines. The HER2-PHF8-IL-6 regulatory axis was active in cell lines and in newly established MMTV-Her2/MMTV-Cre/PHF8fl°x/fl°x mouse models, which revealed the oncogenic function of PHF8 in breast cancer for the first time. Further, the PHF8-IL-6 axis contributed to the resistance to trastuzumab in vitro and may play a critical role in the infiltration of T cells in HER2-driven breast cancers. Interpretation These findings provided informative mechanistic insight into the potential application of PHF8 inhibitors to overcome resistance to anti-HER2 therapies. Funding This work was supported by Carver Trust Young Investigator Award ( 01-224 to H.H.Q); and a Breast Cancer Research Award (to H.H.Q.).
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synergistic interplay between PHF8 and her2 signaling contributes to breast cancer development and drug resistance
bioRxiv, 2019Co-Authors: Qi Liu, Peng Shao, Peterson Kariuki Maina, Nicholas Borcherding, Weizhou ZhangAbstract:Abstract HER2 plays a critical role in tumorigenesis and is associated with poor prognosis of HER2-positive breast cancers. Although, anti-HER2 drugs show benefits in breast cancer therapy, de novo or acquired resistance often develop. Epigenetic factors have been increasingly targeted for therapeutic purposes, however, such mechanisms interacting with HER2 signaling are poorly understood. This study reports the synergistic interplay between histone demethylase PHF8 and HER2 signaling, i.e. PHF8 is elevated in HER2-positive breast cancers and is upregulated by HER2; PHF8 plays coactivator roles in regulating HER2 expression and HER2-driven epithelial-to-mesenchymal transition (EMT) markers and cytokines. The HER2-PHF8-IL-6 regulatory axis was proved both in cell lines and in the newly established MMTV-Her2/MMTV-Cre/PHF8flox/flox models, with which the oncogenic function of PHF8 in breast cancer in vivo was revealed for the first time. Furthermore, PHF8-IL-6 axis contributes to the resistance of Trastuzumab in vitro and may play a critical role in the infiltration of T-cells in HER2-driven breast cancers. This study reveals novel epigenetic mechanisms underlying HER2-driven cancer development and anti-HER2 drug resistance.
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histone demethylase PHF8 regulates hypoxia signaling through hif1α and h3k4me3
Biochimica et Biophysica Acta, 2017Co-Authors: Peterson Kariuki Maina, Peng Shao, Qi Liu, Shaikamjad Umesalma, Xiongfei Jia, Maximo J Marin, Donald Long, Samantha ConcepcionromanAbstract:Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.
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histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis
Nucleic Acids Research, 2017Co-Authors: Peng Shao, Qi Liu, Peterson Kariuki Maina, Jiayue Cui, Thomas B Bair, Shaikamjad Umesalma, Weizhou ZhangAbstract:Histone demethylase PHF8 is upregulated and plays oncogenic roles in various cancers; however, the mechanisms underlying its dysregulation and functions in carcinogenesis remain obscure. Here, we report the novel functions of PHF8 in EMT (epithelial to mesenchymal transition) and breast cancer development. Genome-wide gene expression analysis revealed that PHF8 overexpression induces an EMT-like process, including the upregulation of SNAI1 and ZEB1. PHF8 demethylates H3K9me1, H3K9me2 and sustains H3K4me3 to prime the transcriptional activation of SNAI1 by TGF-β signaling. We show that PHF8 is upregulated and positively correlated with MYC at protein levels in breast cancer. MYC post-transcriptionally regulates the expression of PHF8 via the repression of microRNAs. Specifically, miR-22 directly targets and inhibits PHF8 expression, and mediates the regulation of PHF8 by MYC and TGF-β signaling. This novel MYC/microRNAs/PHF8 regulatory axis thus places PHF8 as an important downstream effector of MYC. Indeed, PHF8 contributes to MYC-induced cell proliferation and the expression of EMT-related genes. We also report that PHF8 plays important roles in breast cancer cell migration and tumor growth. These oncogenic functions of PHF8 in breast cancer confer its candidacy as a promising therapeutic target for this disease.
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c myc drives histone demethylase PHF8 during neuroendocrine differentiation and in castration resistant prostate cancer
Oncotarget, 2016Co-Authors: Peterson Kariuki Maina, Peng Shao, Qi Liu, Ladan Fazli, Scott R Tyler, Moman Nasir, Xuesen DongAbstract:// Peterson Kariuki Maina 1, * , Peng Shao 1, * , Qi Liu 1 , Ladan Fazli 2 , Scott Tyler 1 , Moman Nasir 3 , Xuesen Dong 2 , Hank Heng Qi 1 1 Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA 2 Vancouver Prostate Center, Department of Urology Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada 3 Department of Health and Human Physiology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA * These authors have contributed equally to this work Correspondence to: Hank Heng Qi, email: hank-qi@uiowa.edu Keywords: prostate cancer, NED, CRPC, PHF8, c-MYC Received: May 02, 2016 Accepted: September 20, 2016 Published: September 28, 2016 ABSTRACT Epigenetic factors play critical roles in prostate cancer (PCa) development. However, how they contribute to neuroendocrine differentiation (NED) and castration-resistant PCa (CRPC) is not fully understood. Using bioinformatics and biochemical approaches to analyze cell-based models of NED and CRPC, we found a cluster of epigenetic factors whose expression is downregulated during NED and upregulated in CRPC (i.e. follow a Down-Up pattern). Two histone demethylases within this cluster, PHF8 and KDM3A, are post-transcriptionally regulated by c-MYC through miR-22, which targets both PHF8 and KDM3A . We also found that the c-MYC/miR-22/PHF8 axis is downstream of androgen receptor (AR) signaling in CRPC cells. The co-expression of PHF8 with AR in clinical CRPC samples, normal mouse prostate, and adenocarcinomas of the prostate during PCa progression in a transgenic (TRAMP) mouse model supports the connection between PHF8 and AR. Knockdown of PHF8 impedes cell cycle progression in CRPC cells and has more profound effects on their growth than on the parental LNCaP cell line. Furthermore, PHF8 knockdown sensitizes LNCaP-Abl cells to the AR antagonist enzalutamide. Our data reveal novel mechanisms that underlie the regulation of PHF8 and KDM3A during NED and in CRPC, and support the candidacy of PHF8 as a therapeutic target in CRPC.
Qi Liu - One of the best experts on this subject based on the ideXlab platform.
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contribution of synergism between PHF8 and her2 signalling to breast cancer development and drug resistance
EBioMedicine, 2020Co-Authors: Peng Shao, Qi Liu, Peterson Kariuki Maina, Nicholas Borcherding, Weizhou ZhangAbstract:Abstract Background HER2 plays a critical role in tumourigenesis and is associated with poor prognosis of patients with HER2-positive breast cancers. Although anti-HER2 drugs are beneficial for treating breast cancer, de novo, or acquired resistance often develops. Epigenetic factors are increasingly targeted for therapy; however, such mechanisms that interact with HER2 signalling are poorly understood. Methods RNA sequencing was performed to identify PHF8 targets downstream of HER2 signalling. CHIP-qPCR were used to investigate how PHF8 regulates HER2 transcription. ELISA determined cytokine secretion. Cell-based assay revealed a feed forward loop in HER2 signalling and then evaluated in vivo. Findings We report the synergistic interplay between histone demethylase PHF8 and HER2 signalling. Specifically, PHF8 levels were elevated in HER2-positive breast cancers and upregulated by HER2. PHF8 functioned as a coactivator that regulated the expression of HER2, markers of the HER2-driven epithelial-to-mesenchymal transition and cytokines. The HER2-PHF8-IL-6 regulatory axis was active in cell lines and in newly established MMTV-Her2/MMTV-Cre/PHF8fl°x/fl°x mouse models, which revealed the oncogenic function of PHF8 in breast cancer for the first time. Further, the PHF8-IL-6 axis contributed to the resistance to trastuzumab in vitro and may play a critical role in the infiltration of T cells in HER2-driven breast cancers. Interpretation These findings provided informative mechanistic insight into the potential application of PHF8 inhibitors to overcome resistance to anti-HER2 therapies. Funding This work was supported by Carver Trust Young Investigator Award ( 01-224 to H.H.Q); and a Breast Cancer Research Award (to H.H.Q.).
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synergistic interplay between PHF8 and her2 signaling contributes to breast cancer development and drug resistance
bioRxiv, 2019Co-Authors: Qi Liu, Peng Shao, Peterson Kariuki Maina, Nicholas Borcherding, Weizhou ZhangAbstract:Abstract HER2 plays a critical role in tumorigenesis and is associated with poor prognosis of HER2-positive breast cancers. Although, anti-HER2 drugs show benefits in breast cancer therapy, de novo or acquired resistance often develop. Epigenetic factors have been increasingly targeted for therapeutic purposes, however, such mechanisms interacting with HER2 signaling are poorly understood. This study reports the synergistic interplay between histone demethylase PHF8 and HER2 signaling, i.e. PHF8 is elevated in HER2-positive breast cancers and is upregulated by HER2; PHF8 plays coactivator roles in regulating HER2 expression and HER2-driven epithelial-to-mesenchymal transition (EMT) markers and cytokines. The HER2-PHF8-IL-6 regulatory axis was proved both in cell lines and in the newly established MMTV-Her2/MMTV-Cre/PHF8flox/flox models, with which the oncogenic function of PHF8 in breast cancer in vivo was revealed for the first time. Furthermore, PHF8-IL-6 axis contributes to the resistance of Trastuzumab in vitro and may play a critical role in the infiltration of T-cells in HER2-driven breast cancers. This study reveals novel epigenetic mechanisms underlying HER2-driven cancer development and anti-HER2 drug resistance.
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histone demethylase PHF8 regulates hypoxia signaling through hif1α and h3k4me3
Biochimica et Biophysica Acta, 2017Co-Authors: Peterson Kariuki Maina, Peng Shao, Qi Liu, Shaikamjad Umesalma, Xiongfei Jia, Maximo J Marin, Donald Long, Samantha ConcepcionromanAbstract:Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.
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histone demethylase PHF8 promotes epithelial to mesenchymal transition and breast tumorigenesis
Nucleic Acids Research, 2017Co-Authors: Peng Shao, Qi Liu, Peterson Kariuki Maina, Jiayue Cui, Thomas B Bair, Shaikamjad Umesalma, Weizhou ZhangAbstract:Histone demethylase PHF8 is upregulated and plays oncogenic roles in various cancers; however, the mechanisms underlying its dysregulation and functions in carcinogenesis remain obscure. Here, we report the novel functions of PHF8 in EMT (epithelial to mesenchymal transition) and breast cancer development. Genome-wide gene expression analysis revealed that PHF8 overexpression induces an EMT-like process, including the upregulation of SNAI1 and ZEB1. PHF8 demethylates H3K9me1, H3K9me2 and sustains H3K4me3 to prime the transcriptional activation of SNAI1 by TGF-β signaling. We show that PHF8 is upregulated and positively correlated with MYC at protein levels in breast cancer. MYC post-transcriptionally regulates the expression of PHF8 via the repression of microRNAs. Specifically, miR-22 directly targets and inhibits PHF8 expression, and mediates the regulation of PHF8 by MYC and TGF-β signaling. This novel MYC/microRNAs/PHF8 regulatory axis thus places PHF8 as an important downstream effector of MYC. Indeed, PHF8 contributes to MYC-induced cell proliferation and the expression of EMT-related genes. We also report that PHF8 plays important roles in breast cancer cell migration and tumor growth. These oncogenic functions of PHF8 in breast cancer confer its candidacy as a promising therapeutic target for this disease.
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c myc drives histone demethylase PHF8 during neuroendocrine differentiation and in castration resistant prostate cancer
Oncotarget, 2016Co-Authors: Peterson Kariuki Maina, Peng Shao, Qi Liu, Ladan Fazli, Scott R Tyler, Moman Nasir, Xuesen DongAbstract:// Peterson Kariuki Maina 1, * , Peng Shao 1, * , Qi Liu 1 , Ladan Fazli 2 , Scott Tyler 1 , Moman Nasir 3 , Xuesen Dong 2 , Hank Heng Qi 1 1 Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52246, USA 2 Vancouver Prostate Center, Department of Urology Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada 3 Department of Health and Human Physiology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA * These authors have contributed equally to this work Correspondence to: Hank Heng Qi, email: hank-qi@uiowa.edu Keywords: prostate cancer, NED, CRPC, PHF8, c-MYC Received: May 02, 2016 Accepted: September 20, 2016 Published: September 28, 2016 ABSTRACT Epigenetic factors play critical roles in prostate cancer (PCa) development. However, how they contribute to neuroendocrine differentiation (NED) and castration-resistant PCa (CRPC) is not fully understood. Using bioinformatics and biochemical approaches to analyze cell-based models of NED and CRPC, we found a cluster of epigenetic factors whose expression is downregulated during NED and upregulated in CRPC (i.e. follow a Down-Up pattern). Two histone demethylases within this cluster, PHF8 and KDM3A, are post-transcriptionally regulated by c-MYC through miR-22, which targets both PHF8 and KDM3A . We also found that the c-MYC/miR-22/PHF8 axis is downstream of androgen receptor (AR) signaling in CRPC cells. The co-expression of PHF8 with AR in clinical CRPC samples, normal mouse prostate, and adenocarcinomas of the prostate during PCa progression in a transgenic (TRAMP) mouse model supports the connection between PHF8 and AR. Knockdown of PHF8 impedes cell cycle progression in CRPC cells and has more profound effects on their growth than on the parental LNCaP cell line. Furthermore, PHF8 knockdown sensitizes LNCaP-Abl cells to the AR antagonist enzalutamide. Our data reveal novel mechanisms that underlie the regulation of PHF8 and KDM3A during NED and in CRPC, and support the candidacy of PHF8 as a therapeutic target in CRPC.