Selective inhibition of tumor oncogenes by disruption of super-enhancers.
Selective inhibition of tumor oncogenes by disruption of super-enhancers.
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通过破坏超增强剂的选择性抑制肿瘤基因。
DOI：
10.1016/j.cell.2013.03.036
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发表时间：
2013-04-11
期刊：
影响因子：
64.5
通讯作者：
Young RA
中科院分区：
文献类型：
--
作者：
Lovén J;Hoke HA;Lin CY;Lau A;Orlando DA;Vakoc CR;Bradner JE;Lee TI;Young RA
染色质调节因子已成为癌症治疗的有吸引力的靶点，但尚不清楚为什么抑制这些无处不在的调节因子在肿瘤细胞中具有基因特异性作用。在这里，我们研究了广泛表达的转录共激活子BRD4的抑制如何导致多发性骨髓瘤（MM）中MYC癌基因的选择性抑制。BRD4和Mediator被发现共同占据了数千个与活性基因相关的增强子。它们还共同占据了一小组特别大的超级增强子，这些增强子与MM生物学中突出的基因相关，包括MYC癌基因。用β -溴结构域抑制剂JQ1治疗MM肿瘤细胞导致BRD4在超增强子处的优先丢失，以及随之而来的转录延伸缺陷，这些缺陷优先影响含有超增强子的基因，包括MYC。在许多其他肿瘤细胞的关键致癌驱动因素中发现了超级增强子。这些观察结果对发现针对不同肿瘤类型的超增强子成分的癌症治疗方法具有启示意义。
Chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. Here, we investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of cancer therapeutics directed at components of super-enhancers in diverse tumor types.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
11.4
作者：
Chng, W-J;Huang, G. F.;Chung, T. H.;Ng, S. B.;Gonzalez-Paz, N.;Troska-Price, T.;Mulligan, G.;Chesi, M.;Bergsagel, P. L.;Fonseca, R.
通讯作者：
Fonseca, R.
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
20.3
作者：
Bergsagel, PL;Kuehl, WM;Shaughnessy, J
通讯作者：
Shaughnessy, J
影响因子：
64.8
作者：
通讯作者：
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