BRG1, the ATPase subunit of SWI/SNF chromatin remodeling complex, interacts with HDAC2 to modulate telomerase expression in human cancer cells
BRG1, the ATPase subunit of SWI/SNF chromatin remodeling complex, interacts with HDAC2 to modulate telomerase expression in human cancer cells
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DOI：
10.4161/15384101.2014.946834
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发表时间：
2014-09-15
期刊：
影响因子：
4.3
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
--
作者：
Wu, Shu;Ge, Yuanlong;Zhao, Yong
端粒酶在人类肿瘤的发生和/或发展过程中经常上调，提示端粒酶的抑制可能抑制肿瘤的生长或进展。在这里，我们报告了BRG1，SWI/SNF染色质重塑复合体的ATPase亚单位，是人类癌细胞中hTERT转录的一般抑制因子。BRG1过表达抑制hTERT转录，而BRG1缺失则刺激hTERT转录，导致更高的端粒酶活性和更长的端粒。染色质免疫沉淀分析表明，BRG1与hTERT启动子的转录起始点(TSS)结合，并与组蛋白脱乙酰酶2(HDAC2)形成三元复合体。BRG1重塑染色质结构以促进HDAC2的作用，导致TSS上H3K9ac和H4ac的脱乙酰化，并抑制hTERT转录。另一方面，-catenin与TSS结合并刺激hTERT转录。因此，BRG1/HDAC2和-catenin在TSS中构成了一个操纵装置，在调节hTERT表达方面发挥着相反但互补的作用。这些结果揭示了调节hTERT转录的阴阳机制，并为hTERT在人类癌细胞中的有限转录提供了解释。在体外组织工程的背景下，BRG1/HDAC2可能具有作为抗癌治疗和/或重新激活细胞增殖能力的潜力。
Telomerase is often upregulated during initiation and/or progression of human tumors, suggesting that repression of telomerase might inhibit cancer growth or progression. Here, we report that BRG1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, is a general suppressor of hTERT transcription in human cancer cells. While overexpression of BRG1 inhibits hTERT transcription, depletion of BRG1 stimulates transcription of hTERT, leading to higher telomerase activity and longer telomeres. Chromatin-immunoprecipitation assays revealed that BRG1 binds to the transcription start site (TSS) of the hTERT promoter and forms a ternary complex with histone deacetylase 2 (HDAC2). BRG1 remodels chromatin structure to facilitate the action of HDAC2, leading to deacetylation of H3K9ac and H4ac at the TSS and suppression of hTERT transcription. On the other hand, -catenin binds to the TSS and stimulates hTERT transcription. Thus, BRG1/HDAC2 and -catenin constitute a manipulative apparatus at the TSS to play opposite but complementary roles in regulating hTERT expression. These results uncover a yin-yang mechanism in modulating hTERT transcription and provide explanation for limited transcription of hTERT in human cancer cells. BRG1/HDAC2 may have a potential as an anti-cancer therapeutic and/or for reactivating cellular proliferative capacity in the context of in vitro tissue engineering.