The Experts below are selected from a list of 2109 Experts worldwide ranked by ideXlab platform
Jinke Cheng - One of the best experts on this subject based on the ideXlab platform.
-
sumo specific protease 1 is critical for myeloid derived suppressor cell development and function
Cancer Research, 2019Co-Authors: Xian Huang, Qiuju Fan, Yong Zuo, Guoqiang Chen, Hongsheng Tan, Baijun Dong, Xiuzhi Wang, Wei Xue, Jinke ChengAbstract:Myeloid-derived suppressor cells (MDSC) can suppress immunity and promote tumorigenesis, and their abundance is associated with poor prognosis. In this study, we show that SUMO1/sentrin-specific peptidase 1 (SENP1) regulates the development and function of MDSC. SENP1 deficiency in myeloid cells promoted MDSC expansion in bone marrow, spleen, and other organs. SENP1−/− MDSC showed stronger immunosuppressive activity than SENP1+/+ MDSC; we observed no defects in the differentiation of myeloid precursor cell in SENP1−/− mice. Mechanistically, SENP1-mediated regulation of MDSC was dependent on STAT3 signaling. We identified CD45 as a specific STAT3 phosphatase in MDSC. CD45 was SUMOylated in MDSC and SENP1 could deconjugate SUMOylated CD45. In SENP1−/− MDSC, CD45 was highly SUMOylated, which reduced its phosphatase activity toward STAT3, leading to STAT3-mediated MDSC development and function. These results reveal a suppressive function of SENP1 in modulating MDSC expansion and function via CD45–STAT3 signaling axis. Significance: These findings show that increased SUMOylation of CD45 via loss of SENP1 suppresses CD45-mediated dephosphorylation of STAT3, which promotes MDSC development and function, leading to tumorigenesis.
-
mitotic phosphorylation of senp3 regulates desumoylation of chromosome associated proteins and chromosome stability
Cancer Research, 2018Co-Authors: Bo Wei, Qiuju Fan, Chao Huang, Bin Liu, Yang Wang, Nansong Xia, Guoqiang Chen, Jinke ChengAbstract:Progression of mitotic cell cycle and chromosome condensation and segregation are controlled by posttranslational protein modifications such as phosphorylation and SUMOylation. However, how SUMO isopeptidases (SENP) regulate cell mitotic procession is largely unknown. Here, we demonstrate that precise phosphorylation of SENP3 during mitosis suppresses SENP3 deSUMOylation activity towards chromosome-associated proteins, including topoisomerase IIα (TopoIIα). Cyclin B-dependent kinases 1 and protein phosphatase 1α were identified as the kinase and phosphatase in control of mitotic SENP3 phosphorylation, respectively. SENP3 phosphorylation decreased its interaction with TopoIIα, resulting in reduced SENP3 deSUMOylation activity on TopoIIα. Furthermore, we observed mitotic arrest, increased chromosome instability, and promotion of tumorigenesis in cells expressing a nonphosphorylatable SENP3 mutant. These data show that SENP3 phosphorylation plays a crucial role in regulating the SUMOylation of chromosome-associated proteins and chromosome stability in mitosis.Significance: Phosphorylation of SENP3 regulates SUMOylation of chromosome-associated proteins to maintain genomic stability during mitosis. Cancer Res; 78(9); 2171-8. ©2018 AACR.
-
SENP1 regulates pten stability to dictate prostate cancer development
Oncotarget, 2017Co-Authors: Tasneem Bawakhalfe, Jinke Cheng, Feng Ming Yang, Joan Ritho, Hui Kuan Lin, Edward T H YehAbstract:// Tasneem Bawa-Khalfe 1 , Feng-Ming Yang 2 , Joan Ritho 2 , Hui-Kuan Lin 3,4 , Jinke Cheng 5,6 and Edward T.H. Yeh 2 1 Department of Biology & Biochemistry, Center for Nuclear Receptors & Cell Signaling, University of Houston, Houston, Texas, USA 2 Department of Internal Medicine, The University of Missouri, Columbia, MO, USA 3 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA 5 Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China 6 State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence to: Tasneem Bawa-Khalfe, email: // Edward T.H. Yeh, email: // Keywords : SENP1, PTEN, WWP2, SUMO, prostate carcinogenesis Received : May 27, 2016 Accepted : November 07, 2016 Published : November 10, 2016 Abstract SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptor-dependent and -independent cell proliferation, stabilizes HIF1α, increases VEGF, and supports angiogenesis. However, mice expressing an androgen-responsive promoter driven SENP1-transgene (SENP1-Tg) develop high-grade prostatic intraepithelial neoplasia, but not carcinoma. We now show that tumor suppressive PTEN signaling is induced in SENP1-Tg to enhance prostate epithelial cell apoptosis. SENP1 blocks SUMO1-dependent ubiquitylation and degradation of PTEN. In the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol, where binding to ubiquitin-E3 ligase WWP2 occurs. Concurrently, WWP2 is also SUMOylated, which potentiates its interaction with PTEN. Thus, SENP1 directs ubiquitin-E3-substrate association to control PTEN stability. PTEN serves as a barrier for SENP1-mediated prostate carcinogenesis as SENP1-Tg mice develop invasive carcinomas only after PTEN reduction. Hence, SENP1 modulates multiple facets of carcinogenesis and may serve as a target specifically for aggressive PTEN-deficient PCa.
-
SENP1 promotes proliferation of clear cell renal cell carcinoma through activation of glycolysis
Oncotarget, 2016Co-Authors: Baijun Dong, Xunlei Kang, Wei Xue, Yujing Gao, Hongchang Gao, Jin Zhang, Hua Guo, Mingjian J You, Jinke ChengAbstract:// Baijun Dong 1, * , Yujing Gao 2, * , Xunlei Kang 3, * , Hongchang Gao 4, * , Jin Zhang 1 , Hua Guo 5, 7 , Mingjian J You 5, 6 , Wei Xue 1 , Jinke Cheng 3 , Yiran Huang 1 1 Department of Urology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China 2 Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, Ningxia, China 3 Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China 4 School of Pharmacy, Wenzhou Medical College, Wenzhou, China 5 Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, USA 6 The Graduate School of Biomedical Science, University of Texas MD Anderson Cancer Center, Houston, USA 7 Current address: North Shore LIJ Health System, New York, USA * These authors contributed equally to this work Correspondence to: Yiran Huang, email: huangyiran@renji.com Jinke Cheng, email: jkcheng@shsmu.edu.cn Keywords: SENP1, glycolysis, HIF-1α, clear cell renal cell carcinoma Received: May 29, 2016 Accepted: October 03, 2016 Published: October 12, 2016 ABSTRACT Metabolic shift toward aerobic glycolysis is a fundamental element contributing to the development and progression of clear cell renal cell carcinoma (ccRCC). We and others previously observed enhanced glycolysis and diminished tricarboxylic acid (TCA) cycle activity in ccRCC tissue. Here, by integrated gene expression and metabolomic analyses of 36 matched pairs of tumor and adjacent normal tissues, we showed that expression of Sentrin/SUMO-specific protease 1 (SENP1) is positively associated with glycolysis levels in ccRCC. Moreover, SENP1 knockdown in RCC4/VHL cells downregulated expression of key glycolytic enzymes under normoxic and hypoxic conditions and inhibited cell proliferation under hypoxic conditions, possibly due to ineffective deSUMOylation and stablization of Hif-1α related to the SENP-1 deficiency. Finally, SENP1 expression correlated positively with tumor pathological grade and was an indicator of poor overall survival and advanced tumor progression in ccRCC. Altered VHL gene function is found in 60–90% ccRCC cases of ccRCC, but therapies targeting VHL-related signaling pathways have been ineffective, spurring exploration of alternative pathological signaling events. Our results provide a possible mechanistic explanation for the role of SENP1 in the initiation and development of ccRCC with normal VHL activity, and identifies SENP1 as a potential treatment target for the disease.
-
SENP1 is a crucial regulator for cell senescence through desumoylation of bmi1
Scientific Reports, 2016Co-Authors: Nansong Xia, Jinke Cheng, Baijun Dong, Song Liu, Feifei Wang, Juan Cai, Fengling Chen, Yong ZuoAbstract:Cell senescence can limit proliferative potential and prevent tumorigenesis. Bmi1 is a key regulator in cell senescence by suppressing the Ink4a/Arf locus. However, how to regulate Bmi1 activity in cell senescence is largely unknown. Here, we show that SENP1 plays an important role in cell senescence by regulating Bmi1 SUMOylation. SENP1−/− primary MEF cells show resistance to cell senescence induced by passaging or other senescence inducing signals. SENP1 deficiency also reduces oncogene H-RasV12-induced senescence, and enhances H-RasV12-induced cell transformation. We further show that in SENP1−/− MEFs the expression of p19Arf, an important regulator in p53/p21-mediated cell senescence, is markedly reduced. Meanwhile, we demonstrate that SENP1 can specifically de-SUMOylate Bmi1 and thereby decreases the occupancy of Bmi1 on p19Arf promoter leading to decrease of H2AK119 mono-ubiquitination and up-expression of p19Arf. These data reveal a crucial role of SENP1 in regulation of cell senescence as well as cell transformation.
Song Liu - One of the best experts on this subject based on the ideXlab platform.
-
SENP1 modulates microglia mediated neuroinflammation toward intermittent hypoxia induced cognitive decline through the de sumoylation of nemo
Journal of Cellular and Molecular Medicine, 2021Co-Authors: Tianyun Yang, Jinyuan Sun, Hongwei Wang, Sisen Zhang, Song LiuAbstract:Intermittent hypoxia (IH)-induced cognition decline is related to the neuroinflammation in microglia. SUMOylation is associated with multiple human diseases, which can be reversed by sentrin/SUMO-specific proteases 1 (SENP1). Herein, we investigated the role of SENP1 in IH-induced inflammation and cognition decline. BV-2 microglial cells and mice were used for inflammatory response and cognition function evaluation following IH treatment. Biochemical analysis and Morris water maze methods were used to elaborate the mechanism of SENP1 in IH impairment. Molecular results revealed that IH induced the inflammatory response, as evidenced by the up-regulation of NF-κB activation, IL-1β and TNF-α in vitro and in vivo. Moreover, IH decreased the expression of SENP1, and increased the SUMOylation of NEMO, not NF-κB P65. Moreover, SENP1 overexpression inhibited IH-induced inflammatory response and SUMOylation of NEMO. However, the inhibitions were abolished by siRNA-NEMO. In contrast, SENP1 depletion enhanced IH-induced inflammatory response and SUMOylation of NEMO, accompanying with increased latency and reduced dwell time in mice. Overall, the results demonstrated that SENP1 regulated IH-induced neuroinflammation by modulating the SUMOylation of NEMO, thus activating the NF-κB pathway, revealing that targeting SENP1 in microglia may represent a novel therapeutic strategy for IH-induced cognitive decline.
-
depletion of SENP1 mediated pparγ sumoylation exaggerates intermittent hypoxia induced cognitive decline by aggravating microglia mediated neuroinflammation
Aging, 2021Co-Authors: Hongwei Wang, Sisen Zhang, Wei Xiong, Sitong Hang, Yanmin Wang, Song LiuAbstract:Intermittent hypoxia (IH)-associated cognition decline is related to the neuroinflammation of microglia. SUMOylation is a post-translational modification related to multiple human diseases, which can be reversed by SENP1. Studies showed that SENP1 and PPARγ play essential roles in restricting inflammation by blocking NF-κB activation. However, the mechanism remains unclear. Herein, we investigated the precise mechanism underlying SENP1 and PPARγ in cognitive decline after IH insult. Biochemical analysis results revealed that IH triggered the inflammatory response and neuronal apoptosis, increased the SUMOylation of PPARγ, and decreased the level of PPARγ compared to that in the normoxia group. After SENP1 downregulation, the inflammatory response, neuronal apoptosis and the SUMOylation of PPARγ were enhanced, and the level of PPARγ was further decreased in vitro and in vivo. However, the application of PPARγ agonist, GW1929, abolished the enhancement of inflammation and neuronal apoptosis in vitro. The Morris Water Maze results showed that both IH groups mice exhibited longer latency and shorter dwell-time in the goal quadrant than normoxia groups. Notably, SENP1 downregulation aggravated these alterations. Overall, these results showed that SENP1 played an essential role in IH-associated cognitive dysfunction. SENP1 depletion aggravated neuroinflammation and neuronal apoptosis via promoting the SUMOylation of PPARγ, reducing the level of PPARγ, thus exaggerating IH-induced cognitive decline.
-
SENP1 mediated nemo de sumoylation inhibits intermittent hypoxia induced inflammatory response of microglia in vitro
Journal of Cellular Physiology, 2020Co-Authors: Tianyun Yang, Bo Wei, Jinyuan Sun, Song LiuAbstract:Among the seven small ubiquitin-like modifier (SUMO)-specific proteases (SENPs), our previous work showed that SENP1 suppressed nuclear factor kappa B (NF-κB) activation and alleviates the inflammatory response in microglia. However, the mechanism is still largely unknown. In this study, western blot analysis and enzyme-linked immunosorbent assay were utilized for evaluating the extent of NF-κB activation and expression of proinflammatory cytokines. qPCR and western blot analysis were performed to detect SENP1 expression. Coimmunoprecipitation followed by western blot analysis was applied to measure the changes in SUMOylation of NF-κB essential modulator (NEMO) and P65 in microglia with or without overexpression of SENP1. As the results, we found that intermittent hypoxia (IH) triggered the activation of NF-κB and upregulated the expression levels of tumor necrosis factor-α and interleukin-6. Interestingly, our data indicated that the SUMOylation of NEMO was enhanced by IH while SUMOylation of P65 was not affected. Further, our data showed that overexpression of SENP1 could decrease the extent of NF-κB activation and inhibit the inflammatory response of microglia through regulating the SUMOylation of NEMO. Collectively, this study presents the first report of the SENP1-controlled de-SUMOylation process of NEMO and its critical role in regulating NF-κB activation and proinflammatory cytokines secretion in microglia cells. This study would benefit for clarifying the role of SENP1 in IH-induced activation of microglia, thus providing potential therapeutic targets for obstructive sleep apnea treatment.
-
SENP1 is a crucial regulator for cell senescence through desumoylation of bmi1
Scientific Reports, 2016Co-Authors: Nansong Xia, Jinke Cheng, Baijun Dong, Song Liu, Feifei Wang, Juan Cai, Fengling Chen, Yong ZuoAbstract:Cell senescence can limit proliferative potential and prevent tumorigenesis. Bmi1 is a key regulator in cell senescence by suppressing the Ink4a/Arf locus. However, how to regulate Bmi1 activity in cell senescence is largely unknown. Here, we show that SENP1 plays an important role in cell senescence by regulating Bmi1 SUMOylation. SENP1−/− primary MEF cells show resistance to cell senescence induced by passaging or other senescence inducing signals. SENP1 deficiency also reduces oncogene H-RasV12-induced senescence, and enhances H-RasV12-induced cell transformation. We further show that in SENP1−/− MEFs the expression of p19Arf, an important regulator in p53/p21-mediated cell senescence, is markedly reduced. Meanwhile, we demonstrate that SENP1 can specifically de-SUMOylate Bmi1 and thereby decreases the occupancy of Bmi1 on p19Arf promoter leading to decrease of H2AK119 mono-ubiquitination and up-expression of p19Arf. These data reveal a crucial role of SENP1 in regulation of cell senescence as well as cell transformation.
-
SENP1 inhibits the ih induced apoptosis and nitric oxide production in bv2 microglial cells
Biochemical and Biophysical Research Communications, 2015Co-Authors: Song Liu, Zhonghua Wang, Kui Chen, Jinyuan Sun, Lianping RenAbstract:To reveal SUMOylation and the roles of Sentrin-specific proteases (SENP)s in microglial cells under Intermittent hypoxia (IH) condition would provide more intensive view of understanding the mechanisms of IH-induced central nervous system (CNS) damage. Hence, in the present study, we detected the expression levels of SENPs in microglial cells under IH and normoxia conditions via RT-PCR assay. We found that SENP1 was significantly down-regulated in cells exposure to IH. Subsequently, the effect of IH for the activation of microglia and the potential roles of SENP1 in the SENP1-overexpressing cell lines were investigated via Western blotting, RT-PCR and Griess assay. The present study demonstrated the apoptosis-inducing and activating role of IH on microglia. In addition, we revealed that the effect of IH on BV-2 including apoptosis, nitric oxide synthase (iNOS) expression and nitric oxide (NO) induction can be attenuated by SENP1 overexpression. The results of the present study are of both theoretical and therapeutic significance to explore the potential roles of SENP1 under IH condition and elucidated the mechanisms underlying microglial survival and activation.
Edward T H Yeh - One of the best experts on this subject based on the ideXlab platform.
-
SENP1 regulates pten stability to dictate prostate cancer development
Oncotarget, 2017Co-Authors: Tasneem Bawakhalfe, Jinke Cheng, Feng Ming Yang, Joan Ritho, Hui Kuan Lin, Edward T H YehAbstract:// Tasneem Bawa-Khalfe 1 , Feng-Ming Yang 2 , Joan Ritho 2 , Hui-Kuan Lin 3,4 , Jinke Cheng 5,6 and Edward T.H. Yeh 2 1 Department of Biology & Biochemistry, Center for Nuclear Receptors & Cell Signaling, University of Houston, Houston, Texas, USA 2 Department of Internal Medicine, The University of Missouri, Columbia, MO, USA 3 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA 5 Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China 6 State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence to: Tasneem Bawa-Khalfe, email: // Edward T.H. Yeh, email: // Keywords : SENP1, PTEN, WWP2, SUMO, prostate carcinogenesis Received : May 27, 2016 Accepted : November 07, 2016 Published : November 10, 2016 Abstract SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptor-dependent and -independent cell proliferation, stabilizes HIF1α, increases VEGF, and supports angiogenesis. However, mice expressing an androgen-responsive promoter driven SENP1-transgene (SENP1-Tg) develop high-grade prostatic intraepithelial neoplasia, but not carcinoma. We now show that tumor suppressive PTEN signaling is induced in SENP1-Tg to enhance prostate epithelial cell apoptosis. SENP1 blocks SUMO1-dependent ubiquitylation and degradation of PTEN. In the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol, where binding to ubiquitin-E3 ligase WWP2 occurs. Concurrently, WWP2 is also SUMOylated, which potentiates its interaction with PTEN. Thus, SENP1 directs ubiquitin-E3-substrate association to control PTEN stability. PTEN serves as a barrier for SENP1-mediated prostate carcinogenesis as SENP1-Tg mice develop invasive carcinomas only after PTEN reduction. Hence, SENP1 modulates multiple facets of carcinogenesis and may serve as a target specifically for aggressive PTEN-deficient PCa.
-
induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy
Journal of Molecular and Cellular Cardiology, 2015Co-Authors: Rong Cai, Edward T H Yeh, Xiaobing Liu, Song Xue, Haipeng Sun, Wenhan Mei, Shuxun Ren, Joseph E Rabinowitz, Yibin WangAbstract:Defect in mitochondrial biogenesis and cardiac energy metabolism is a critical contributing factor to cardiac hypertrophy and heart failure. Sentrin/SUMO specific protease 1 (SENP1) mediated regulation of PGC-1α transcriptional activity plays an essential role in mitochondrial biogenesis and mitochondrial function. However, whether SENP1 plays a role in cardiac hypertrophy and failure is unknown. We investigated whether alteration in SENP1 expression affects cardiomyopathy and the underlying mechanism. In our present study, we found that the expression of SENP1 was induced in mouse and human failing hearts associated with induced expression of mitochondrial genes. SENP1 expression in cardiomyocytes was induced by hypertrophic stimuli through calcium/calcineurin-NFAT3. SENP1 regulated mitochondrial gene expression by de-SUMOylation of MEF-2C, which enhanced MEF-2C-mediated PGC-1α transcription. Genetic induction of SENP1 led to mitochondrial dysregulation and cardiac dysfunction in vivo. Our data showed that pathogenesis of cardiomyopathy is attributed by SENP1 mediated regulation of mitochondrial abnormities. SENP1 up-regulation in diseased heart is mediated via calcineurin-NFAT/MEF2C-PGC-1α pathway.
-
induction of SENP1 in endothelial cells contributes to hypoxia driven vegf expression and angiogenesis
Journal of Biological Chemistry, 2010Co-Authors: Yong Zuo, Xunlei Kang, Edward T H Yeh, Guoqiang Chen, Haizeng Zhang, Fei Yue, Mingyao Liu, Jinke ChengAbstract:SENP1 (SUMO-specific protease 1) has been shown to be essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1α) under hypoxia conditions. However, it is unknown how SENP1 activation and hypoxia signaling are coordinated in the cellular response to hypoxia. Here, we report the essential role of SENP1 in endothelial cells as a positive regulator of hypoxia-driven VEGF production and angiogenesis. SENP1 expression is increased in endothelial cells following exposure to hypoxia. Silencing of HIF-1α blocks SENP1 expression in cell response to hypoxia. Mutation of the hypoxia response element (HRE) on the SENP1 promoter abolishes its transactivation in response to hypoxia. Moreover, silencing of SENP1 expression decreases VEGF production and abrogates the angiogenic functions of endothelial cell. We also find that the elongated endothelial cells in embryonic brain section and vascular endothelial cells in embryonic renal glomeruli in SENP1−/− mice are markedly reduced than those in wild-type. Thus, these results show that hypoxia implies a positive feedback loop mediated by SENP1. This feedback loop is important in VEGF production, which is essential for angiogenesis in endothelial cells.
-
senp3 is responsible for hif 1 transactivation under mild oxidative stress via p300 de sumoylation
The EMBO Journal, 2009Co-Authors: Chao Huang, Xuxu Sun, Yan Han, Yumei Wang, Shan Yan, Edward T H Yeh, Yuying Chen, Hui Cang, Guiying Shi, Jinke ChengAbstract:The physiological function of Sentrin/SUMO-specific proteases (SENPs) remains largely unexplored, and little is known about the regulation of SENPs themselves. Here, we show that a modest increase of reactive oxygen species (ROS) regulates SENP3 stability and localization. We found that SENP3 is continuously degraded through the ubiquitin-proteasome pathway under basal condition and that ROS inhibit this degradation. Furthermore, ROS causes SENP3 to redistribute from the nucleoli to the nucleoplasm, allowing it to regulate nuclear events. The stabilization and redistribution of SENP3 correlate with an increase in the transcriptional activity of the hypoxia-inducing factor-1 (HIF-1) under mild oxidative stress. ROS-enhanced HIF-1 transactivation is blocked by SENP3 knockdown. The de-SUMOylating activity of SENP3 is required for ROS-induced increase of HIF-1 transactivation, but the true substrate of SENP3 is the co-activator of HIF-1α, p300, rather than HIF-1α itself. Removing SUMO2/3 from p300 enhances its binding to HIF-1α. In vivo nude mouse xenografts overexpressing SENP3 are more angiogenic. Taken together, our results identify SENP3 as a redox sensor that regulates HIF-1 transcriptional activity under oxidative stress through the de-SUMOylation of p300.
Hongwei Wang - One of the best experts on this subject based on the ideXlab platform.
-
SENP1 modulates microglia mediated neuroinflammation toward intermittent hypoxia induced cognitive decline through the de sumoylation of nemo
Journal of Cellular and Molecular Medicine, 2021Co-Authors: Tianyun Yang, Jinyuan Sun, Hongwei Wang, Sisen Zhang, Song LiuAbstract:Intermittent hypoxia (IH)-induced cognition decline is related to the neuroinflammation in microglia. SUMOylation is associated with multiple human diseases, which can be reversed by sentrin/SUMO-specific proteases 1 (SENP1). Herein, we investigated the role of SENP1 in IH-induced inflammation and cognition decline. BV-2 microglial cells and mice were used for inflammatory response and cognition function evaluation following IH treatment. Biochemical analysis and Morris water maze methods were used to elaborate the mechanism of SENP1 in IH impairment. Molecular results revealed that IH induced the inflammatory response, as evidenced by the up-regulation of NF-κB activation, IL-1β and TNF-α in vitro and in vivo. Moreover, IH decreased the expression of SENP1, and increased the SUMOylation of NEMO, not NF-κB P65. Moreover, SENP1 overexpression inhibited IH-induced inflammatory response and SUMOylation of NEMO. However, the inhibitions were abolished by siRNA-NEMO. In contrast, SENP1 depletion enhanced IH-induced inflammatory response and SUMOylation of NEMO, accompanying with increased latency and reduced dwell time in mice. Overall, the results demonstrated that SENP1 regulated IH-induced neuroinflammation by modulating the SUMOylation of NEMO, thus activating the NF-κB pathway, revealing that targeting SENP1 in microglia may represent a novel therapeutic strategy for IH-induced cognitive decline.
-
depletion of SENP1 mediated pparγ sumoylation exaggerates intermittent hypoxia induced cognitive decline by aggravating microglia mediated neuroinflammation
Aging, 2021Co-Authors: Hongwei Wang, Sisen Zhang, Wei Xiong, Sitong Hang, Yanmin Wang, Song LiuAbstract:Intermittent hypoxia (IH)-associated cognition decline is related to the neuroinflammation of microglia. SUMOylation is a post-translational modification related to multiple human diseases, which can be reversed by SENP1. Studies showed that SENP1 and PPARγ play essential roles in restricting inflammation by blocking NF-κB activation. However, the mechanism remains unclear. Herein, we investigated the precise mechanism underlying SENP1 and PPARγ in cognitive decline after IH insult. Biochemical analysis results revealed that IH triggered the inflammatory response and neuronal apoptosis, increased the SUMOylation of PPARγ, and decreased the level of PPARγ compared to that in the normoxia group. After SENP1 downregulation, the inflammatory response, neuronal apoptosis and the SUMOylation of PPARγ were enhanced, and the level of PPARγ was further decreased in vitro and in vivo. However, the application of PPARγ agonist, GW1929, abolished the enhancement of inflammation and neuronal apoptosis in vitro. The Morris Water Maze results showed that both IH groups mice exhibited longer latency and shorter dwell-time in the goal quadrant than normoxia groups. Notably, SENP1 downregulation aggravated these alterations. Overall, these results showed that SENP1 played an essential role in IH-associated cognitive dysfunction. SENP1 depletion aggravated neuroinflammation and neuronal apoptosis via promoting the SUMOylation of PPARγ, reducing the level of PPARγ, thus exaggerating IH-induced cognitive decline.
Li-sheng Wang - One of the best experts on this subject based on the ideXlab platform.
-
SENP1 regulates hepatocyte growth factor-induced migration and epithelial-mesenchymal transition of hepatocellular carcinoma
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2015Co-Authors: Wenwen Zhang, Hui-yan Sun, Xue-feng Shi, Hua Wang, Chunping Cui, Fengjun Xiao, Xiaozhong Guo, Li-sheng WangAbstract:The deregulation of HGF/c-Met signaling is implicated in epithelial-mesenchymal transition (EMT) and progress of hepatocellular carcinoma (HCC). However, the epigenetic mechanisms that HGF/c-Met regulates EMT and metastasis of HCC cells are less explored. In this study, we demonstrated that HCC cells express a high level of SUMO/sentrin-specific protease 1 (SENP1) which is induced by HGF/c-Met signals. Lentivirus-mediated small hairpin RNA (shRNA) transduction results in SENP1 silence in HCC cells. SENP1 silence reduces the HGF-induced proliferation and migration of HCC cells. SENP1 inhibition also induces HCC cell apoptosis and growth arrest. Furthermore, SENP1 knockdown inhibits epithelial-to-mesenchymal transition, with increase of E-cadherin and ZO-1 expression, decrease of fibronectin and N-cadherin expression. The EMT-related transcription factor Zeb1 was SUMO-modified and decreased in SENP1-silenced HCC cells. These results delineate that SENP1 might play an important role in the regulation of HGF-induced invasion and migration of HCC cells.
-
589 SENP1 knockdown inhibits hepatocyte growth factor induced migration and epithelial mesenchymal transition of hepatocellular carcinoma
Molecular Therapy, 2015Co-Authors: Wenwen Zhang, Hui-yan Sun, Hua Wang, Chunping Cui, Fengjun Xiao, Xiaozhong Guo, Li-sheng WangAbstract:The hepatocyte growth factor (HGF)/c-Met signaling aberrations are implicated in the pathogenesis and progress of hepatocellular carcinoma (HCC). However, the epigenetic regulators and their roles in modulating HGF-induced epithelial-mesenchymal transition (EMT), invasion and metastasis of HCC cells are less explored. SUMO/sentrin specific protease 1 (SENP1) is the cysteine protease that regulates SUMO pathways by deconjugating sumoylated proteins. Using real-time PCR we identified increased expression of SENP1 and c-Met in HCC tumors compared to adjacent noncancerous tissues (p<0.05, n=20). We further demonstrated that SENP1 overexpression is associated with HGF/c-Met signals in HCC. Treatment of HCC cells with HGF results in upregulation of SENP1 in a stat5 dependent manner. To explore the role of SENP1 in regulation of characteristics of HCC cells, we knocked down SENP1 in HCC cells lines using lentiviral vectors pLKO. 1-GFP-SENP1-shRNA. HCC-LM3 cells transduced with this vector demonstrated 77% decreased expression of SENP1 compared to cells transduced with a control vector. Lentivirus-mediated SENP1 knockdown triggers apoptosis (from control with 7.68% to SENP1 shRNA with 20.4%), cell cycle arrest and inhibits proliferation (80.6% inhibition, p<0.01) of HCC cells. SENP1 silence reduces HGF-induced migration of HCC cells (66.7% inhibition, p<0.01). Importantly, SENP1 inhibition increases E-cadherin and ZO-1 expression, and decrease fibronectin and N-cadherin expression in HCC cells. A series of transcription factors are involved in regulation of EMT processes. Zeb1 is a zinc finger transcription factor which induces an EMT and confers a metastatic phenotype on carcinomas. We predicted the sumoylation sites of Zeb1 by using a site-specific predictor of SUMOsp 2.0. This prediction was further validated by using Zeb-1 immunoprecipitation and Sumo2 antibody blot. HGF treatment also induced the expression of zeb1. SENP1 knockdown increased Zeb1 desumoylation, leading to reduce its protein level in HCC cells.Our results indicate that SENP1 is frequently over-expressed and associated with HGF/C-met in HCC. SENP1 plays a key role in HGF-induced proliferation, migration and epithelial-mesenchymal transition, suggesting it may be a potential new therapeutic target for HCC.
