TY - JOUR
T1 - Regulation of USP37 expression by REST-associated G9a-dependent histone methylation
AU - Dobson, Tara Heather
AU - Hatcher, Rashieda Jonine
AU - Swaminathan, Jyothishmathi
AU - Das, Chandra M.
AU - Shaik, Shavali
AU - Tao, Rong Hua
AU - Milite, Ciro
AU - Castellano, Sabrina
AU - Taylor, Pete H.
AU - Sbardella, Gianluca
AU - Gopalakrishnan, Vidya
N1 - Funding Information:
The authors thank Dr. Xiaobing Shi for providing reagents and Dr. Mark Bedford for helpful comments. This work was supported by grants from the NIH (5R01-NS-079715-01), American Cancer Society (RSG-09-273-01-DDC) and Cancer Prevention Research Institute of Texas (CPRIT-RP150301) to V. Gopalakrishnan, The UT MD Anderson Cancer Center-CCE Scholar Program (to T.H.W. Dobson), and Cancer Center support grant NCI#CA16672 (to the Characterized Cell Line Core). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/8
Y1 - 2017/8
N2 - The deubiquitylase (DUB) USP37 is a component of the ubiquitin system and controls cell proliferation by regulating the stability of the cyclin-dependent kinase inhibitor 1B, (CDKN1B/p27Kip1). The expression of USP37 is downregulated in human medulloblastoma tumor specimens. In the current study, we show that USP37 prevents medulloblastoma growth in mouse orthotopic models, suggesting that it has tumor-suppressive properties in this neural cancer. Here, we also report on the mechanism underlying USP37 loss in medulloblastoma. Previously, we observed that the expression of USP37 is transcriptionally repressed by the RE1 silencing transcription factor (REST), which requires chromatin remodeling factors for its activity. Genetic and pharmacologic approaches were employed to identify a specific role for G9a, a histone methyltransferase (HMT), in promoting methylation of histone H3 lysine-9 (H3K9) mono- and dimethylation, and surprisingly trimethylation, at the USP37 promoter to repress its gene expression. G9a inhibition also blocked the tumorigenic potential of medulloblastoma cells in vivo. Using isogenic low- and high-REST medulloblastoma cells, we further showed a REST-dependent elevation in G9a activity, which further increased mono- and trimethylation of histone H3K9, accompanied by downregulation of USP37 expression. Together, these findings reveal a role for REST-associated G9a and histone H3K9 methylation in the repression of USP37 expression in medulloblastoma.
AB - The deubiquitylase (DUB) USP37 is a component of the ubiquitin system and controls cell proliferation by regulating the stability of the cyclin-dependent kinase inhibitor 1B, (CDKN1B/p27Kip1). The expression of USP37 is downregulated in human medulloblastoma tumor specimens. In the current study, we show that USP37 prevents medulloblastoma growth in mouse orthotopic models, suggesting that it has tumor-suppressive properties in this neural cancer. Here, we also report on the mechanism underlying USP37 loss in medulloblastoma. Previously, we observed that the expression of USP37 is transcriptionally repressed by the RE1 silencing transcription factor (REST), which requires chromatin remodeling factors for its activity. Genetic and pharmacologic approaches were employed to identify a specific role for G9a, a histone methyltransferase (HMT), in promoting methylation of histone H3 lysine-9 (H3K9) mono- and dimethylation, and surprisingly trimethylation, at the USP37 promoter to repress its gene expression. G9a inhibition also blocked the tumorigenic potential of medulloblastoma cells in vivo. Using isogenic low- and high-REST medulloblastoma cells, we further showed a REST-dependent elevation in G9a activity, which further increased mono- and trimethylation of histone H3K9, accompanied by downregulation of USP37 expression. Together, these findings reveal a role for REST-associated G9a and histone H3K9 methylation in the repression of USP37 expression in medulloblastoma.
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U2 - 10.1158/1541-7786.MCR-16-0424
DO - 10.1158/1541-7786.MCR-16-0424
M3 - Article
C2 - 28483947
AN - SCOPUS:85026641347
SN - 1541-7786
VL - 15
SP - 1073
EP - 1084
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -