SUMO protease SENP1 deSUMOylates and stabilizes c-Myc

Sun, Xiao Xin; Chen, Yingxiao; Su, Yulong; Wang, Xiaoyan; Chauhan, Krishna M.; Liang, Juan Boo; Daniel, Colin J.; Sears, Rosalie C.; Dai, Mu Shui

doi:10.1073/pnas.1802932115

Cited by 67 publications

(74 citation statements)

References 32 publications

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“…Overexpression of SENP1 has been shown to regulate glycolysis in prostatic carcinoma cells by stabilizing HIF1α [14]. SENP1 was been found to be a crucial c-Myc deSUMOylating enzyme that positively regulates c-Myc stability and activity in breast cancer [11]. In our study, SIrt6 could be SUMOylated in lung adenocarcinoma, and the mutation of SUMOylation sites in Sirt6 decreased its tumor-suppressive activity.…”

Section: Discussionsupporting

confidence: 47%

“…It can affect cancer-related processes such as cellular proliferation and invasion [5,14]. In our study silencing of [11]. Overexpression of SENP1 has been shown to regulate glycolysis in prostatic carcinoma cells by stabilizing HIF1α [14].…”

Section: Discussionmentioning

confidence: 61%

“…Knockdown of SENP1 suppresses cell proliferation and transformation in breast cancer cell lines [11].…”

Section: Discussionmentioning

confidence: 99%

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SENP1 Knockdown Suppresses Tumor Progression in Lung Adenocarcinoma by Regulating AAR Genes Expression

Chen¹,

Li²,

Yu³

et al. 2020

Preprint

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Background SUMO specific peptidase 1(SENP1) is an important factor involved in the regulation of small ubiquitin-related modifier (SUMO) modification. Our previous research has shown that SENP1 could be a potential tumor-promoting factor in non-small cell lung cancer (NSCLC). However, its role in tumor progression remains largely unknown. This study aims to characterize the role of SENP1 in lung adenocarcinoma. Methods The TCGA database provided us expression profiles of SENP1 and overall survival rates. loss-of-function assays were performed to examine the effect of SENP1 on proliferation, migration and invasion of lung adenocarcinoma cells in vitro and in vivo. Immunoprecipitation (IP), western blot and quantitative real time PCR (qRT-PCR) were carried out to reveal the interrelation between SENP1, SIRT6 and AAR (amino acid response) genes signal pathway. Results In this study, we found that SENP1 was expressed at high levels in lung adenocarcinoma tissues and advanced TNM stages and was significantly associated with poor prognosis. we also found that SENP1 knockdown inhibited lung adenocarcinoma cell progression in vitro and in vivo. SUMOylation of SIRT6 was also observed in lung adenocarcinoma, and it was reduced by SENP1. SUMOylation of SIRT6 specifically increased its deacetylation of histone H3 on lysine 56 instead of that of lysine 9 (H3K9) in an in vitro model. Mechanistically, we found that knockdown of SENP1 reduced the expression of AAR genes by decreasing H3K56 acetylation through increasing SIRT6 SUMOylation. Moreover, mutation of the SUMOylation sites of Sirt6 reduced its tumor-suppressive effects. Conclusions These results revealed that SENP1 promotion of tumor progression in lung adenocarcinoma and its tumor-promoting effects might be attributed to its important role in the regulation of Sirt6 SUMOylation and the expression of AAR genes.

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Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 61%

See 1 more Smart Citation

SENP1 Knockdown Suppresses Tumor Progression in Lung Adenocarcinoma by Regulating AAR Genes Expression

Chen¹,

Li²,

Yu³

et al. 2020

Preprint

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“…Similarly, USP7 has been shown to bind and stabilize N-MYC and inhibition of this DUB decreases N-MYC driven tumorigenesis in vivo [180]. Another strategy to affect MYC ubiquitination involves modulation of the small ubiquitin-related modifier (SUMO), where we have discovered that inhibition of the deSUMOylation enzyme SENP1, which is overexpressed in human breast cancer cells and increases MYC stability and transactivation activity, stimulated MYC ubiquitination and increased MYC degradation, providing a new strategy for MYC protein degradation [181]. Finally, the Aurora-A kinase inhibitors MLN8054 and MLN8237 have been shown to affect both c-MYC and N-MYC ubiquitin-mediated degradation independent of their kinase activity [182][183][184][185][186][187][188].…”

Section: Targeting Myc Stabilitymentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

Self Cite

134

110

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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“…SUMOylation has been reported to alter subcellular/subnuclear distribution, stability, transcriptional activity, or protein-protein interaction of TFs [36][37][38][39][40]. The protein Olig2 SUMOylation has no effect on TSM phosphorylation, but suppresses the overall serine phosphorylation of Olig2.…”

Section: Olig2 Sumoylation Does Not Alter Its Stability Subcellularmentioning

confidence: 99%

Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting

et al. 2020

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Posttranslational modifications of nuclear proteins, including transcription factors, nuclear receptors, and their coregulators, have attracted much attention in cancer research. Although phosphorylation of oligodendrocyte transcription factor 2 (Olig2) may contribute to the notorious resistance of gliomas to radiation and genotoxic drugs, the precise mechanisms remain elusive. We show here that in addition to phosphorylation, Olig2 is also conjugated by small ubiquitin-like modifier-1 (SUMO1) at three lysine residues K27, K76, and K112. SUMOylation is required for Olig2 to suppress p53-mediated cell cycle arrest and apoptosis induced by genotoxic damage, and to enhance resistance to temozolomide (TMZ) in glioma. Both SUMOylation and triple serine motif (TSM) phosphorylation of Olig2 are required for the antiapoptotic function. Olig2 SUMOylation enhances its genetic targeting ability, which in turn occludes p53 recruitment to Cdkn1a promoter for DNA-damage responses. Our work uncovers a SUMOylation-dependent regulatory mechanism of Olig2 in regulating cancer survival.

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SUMO protease SENP1 deSUMOylates and stabilizes c-Myc

Cited by 67 publications

References 32 publications

SENP1 Knockdown Suppresses Tumor Progression in Lung Adenocarcinoma by Regulating AAR Genes Expression

SENP1 Knockdown Suppresses Tumor Progression in Lung Adenocarcinoma by Regulating AAR Genes Expression

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting

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