Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma
Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma
复制标题
溴结构域和末端外蛋白促进核心转录调控程序并赋予脂肪肉瘤脆弱性
DOI：
10.1038/s41467-019-09257-z
复制
发表时间：
2019-03-22
影响因子：
16.6
通讯作者：
Koeffler, H. Phillip
中科院分区：
文献类型：
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作者：
Chen, Ye;Xu, Liang;Koeffler, H. Phillip
脂肪肉瘤是一组向脂肪细胞分化的恶性间质肿瘤。在这里，为了深入了解这种疾病中的增强子失调和转录成瘾，我们绘制了LPS组织和细胞系中的超级增强子结构。我们鉴定了粘液样LPS中的溴结构域和末端外（BET）蛋白协同的FUS-DDIT 3功能和去分化LPS中的由FOSL 2、MYC和RUNX 1组成的BET蛋白依赖的核心转录调控回路。此外，SNAI 2被鉴定为对去分化LPS细胞实施增殖和转移潜能的关键下游靶标。BET基因、核心转录因子或SNAI 2的遗传缺失一致地减轻LPS恶性肿瘤。我们还揭示了LPS细胞对BET蛋白降解剂ARV-825的令人信服的易感性。BET蛋白质消耗赋予了额外的优势，以避免对LPS的化疗药物Trabectedin的获得性耐药性。此外，这项研究提供了一个框架，发现和靶向的核心致癌转录程序在人类癌症。
Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.