Dobson Tara H W, Hatcher Rashieda J, Swaminathan Jyothishmathi, Das Chandra M, Shaik Shavali, Tao Rong-Hua, Milite Ciro, Castellano Sabrina, Taylor Pete H, Sbardella Gianluca, Gopalakrishnan Vidya
Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, Texas.
Epigenetic Medicinal Chemistry Lab, Dipartimento di Farmacia, Università degli Studi di Salerno, Fisciano (SA), Italy.
Mol Cancer Res. 2017 Aug;15(8):1073-1084. doi: 10.1158/1541-7786.MCR-16-0424. Epub 2017 May 8.
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 loss in medulloblastoma. Previously, we observed that the expression of is transcriptionally repressed by the 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 promoter to repress its gene expression. G9a inhibition also blocked the tumorigenic potential of medulloblastoma cells 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 expression. Together, these findings reveal a role for REST-associated G9a and histone H3K9 methylation in the repression of expression in medulloblastoma. Reactivation of USP37 by G9a inhibition has the potential for therapeutic applications in REST-expressing medulloblastomas. .
去泛素化酶（DUB）USP37是泛素系统的一个组成部分，通过调节细胞周期蛋白依赖性激酶抑制剂1B（CDKN1B/p27Kip1）的稳定性来控制细胞增殖。USP37的表达在人类髓母细胞瘤肿瘤标本中下调。在本研究中，我们表明USP37在小鼠原位模型中可阻止髓母细胞瘤生长，这表明它在这种神经癌中具有肿瘤抑制特性。在此，我们还报告了髓母细胞瘤中USP37缺失的潜在机制。此前，我们观察到USP37的表达受到沉默转录因子（REST）的转录抑制，而REST的活性需要染色质重塑因子。我们采用基因和药理学方法来确定组蛋白甲基转移酶（HMT）G9a在促进组蛋白H3赖氨酸-9（H3K9）单甲基化和二甲基化以及令人惊讶的三甲基化方面的具体作用，从而在USP37启动子处抑制其基因表达。抑制G9a也阻断了髓母细胞瘤细胞的致瘤潜力。利用同基因的低REST和高REST髓母细胞瘤细胞，我们进一步表明G9a活性在REST依赖的情况下升高，这进一步增加了组蛋白H3K9的单甲基化和三甲基化，同时伴随着USP37表达的下调。总之，这些发现揭示了REST相关的G9a和组蛋白H3K9甲基化在髓母细胞瘤中USP37表达抑制中的作用。通过抑制G9a重新激活USP37在表达REST的髓母细胞瘤中具有治疗应用潜力。
