Division of Cancer Genetics and Therapeutics, Laboratory of NFκB Signaling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.
Cancer Discov. 2016 Nov;6(11):1276-1291. doi: 10.1158/2159-8290.CD-16-0177. Epub 2016 Sep 20.
Cancer-specific TERT promoter mutations (-146C>T and -124C>T) have been linked to reactivation of the epigenetically silenced telomerase reverse transcriptase gene (TERT). Understanding how these single-nucleotide alterations drive TERT reactivation is a fundamental unanswered question and is key for making successful therapeutics. We show that unlike wild-type promoters, recruitment of the transcription factor GABPA specifically to mutant TERT promoters mediates long-range chromatin interaction and enrichment of active histone marks, and hence drives TERT transcription. CRISPR-mediated reversal of mutant TERT promoters, or deletion of its long-range interacting chromatin, abrogates GABPA binding and long-range interactions, leading to depletion of active histone marks, loss of POL2 recruitment, and suppression of TERT transcription. In contrast, de novo introduction of a TERT promoter mutation enables GABPA binding and upregulation of TERT via long-range interactions, acquisition of active histone marks, and subsequent POL2 recruitment. This study provides a unifying mechanistic insight into activation of mutant TERT promoters across various human cancers.
This study identifies a key mechanism by which cancer-specific mutant TERT promoters cause reactivation of TERT Because the mechanism uncovered here is not utilized by promoters that drive TERT in normal cells, this mechanism could be exploited to make inhibitors which have the potential to block telomerase function and hence the progression of up to 90% of human cancers. Cancer Discov; 6(11); 1276-91. ©2016 AACR.See related commentary by Min and Shay, p. 1212This article is highlighted in the In This Issue feature, p. 1197.
癌症特异性 TERT 启动子突变（-146C>T 和-124C>T）与表观遗传沉默的端粒酶逆转录酶基因（TERT）的重新激活有关。了解这些单核苷酸改变如何驱动 TERT 重新激活是一个基本的未解决的问题，也是成功制作治疗药物的关键。我们表明，与野生型启动子不同，转录因子 GABPA 特异性募集到突变 TERT 启动子介导长距离染色质相互作用和活性组蛋白标记的富集，从而驱动 TERT 转录。CRISPR 介导的突变 TERT 启动子逆转，或其长距离相互作用染色质的缺失，消除了 GABPA 结合和长距离相互作用，导致活性组蛋白标记物的耗竭、POL2 募集的丧失以及 TERT 转录的抑制。相比之下，通过长距离相互作用、获得活性组蛋白标记物以及随后的 POL2 募集，新引入的 TERT 启动子突变可使 GABPA 结合并上调 TERT。这项研究为各种人类癌症中突变 TERT 启动子的激活提供了一个统一的机制见解。
这项研究确定了癌症特异性突变 TERT 启动子导致 TERT 重新激活的关键机制。由于这里发现的机制未被驱动正常细胞中 TERT 的启动子利用，因此可以利用该机制来制作抑制剂，这些抑制剂有可能阻断端粒酶功能，从而阻止多达 90%的人类癌症的进展。癌症发现；6(11)；1276-91。©2016AACR。请参阅 Min 和 Shay 相关评论，第 1212 页。本文在本期特色文章中突出显示，第 1197 页。
