小柯机器人

美国冷泉港实验室Alea A. Mills研究团队发现，BRD8通过p53网络的表观遗传学重编程维持胶质母细胞瘤。2022年12月21日，《自然》杂志在线发表了这项成果。

研究人员表示，抑制p53（由TP53编码）的肿瘤抑制功能对人类的癌症发展至关重要。然而，在胶质母细胞瘤（GBM），即最常见和最致命的成人脑部恶性肿瘤的大多数病例中，p53仍然没有发生突变。因此，在TP53野生型（TP53^WT）的GBM中，p53介导的肿瘤抑制是如何被对抗的还不清楚。

研究人员描述了一种GBM特有的表观遗传机制，其中染色质调节器含溴域蛋白8（BRD8）通过EP400组蛋白乙酰转移酶复合物维持P53靶点上的H2AZ占据。这种机制造成了一种抑制性染色质状态，阻止了p53的转导，维持了增殖。值得注意的是，靶向BRD8的溴域取代了H2AZ，增强了染色质的可及性，并使p53转录激活。这反过来又加强了TP53^WT GBM的细胞周期停止和肿瘤抑制。与这些发现一致，BRD8与H2AZ在患者来源的GBM的增殖单细胞中高度表达，并与CDKN1A成反比，后者是编码p21的经典p53靶点。这项工作确定了BRD8是一种恶性肿瘤的选择性表观遗传弱点，而这种恶性肿瘤的治疗几十年来一直没有改善。此外，针对BRD8的溴域可能是TP53^WT GBM患者的一个潜在治疗策略。

附：英文原文

Title: BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network

Author: Sun, Xueqin, Klingbeil, Olaf, Lu, Bin, Wu, Caizhi, Ballon, Carlos, Ouyang, Meng, Wu, Xiaoli S., Jin, Ying, Hwangbo, Yon, Huang, Yu-Han, Somerville, Tim D. D., Chang, Kenneth, Park, Jung, Chung, Taemoon, Lyons, Scott K., Shi, Junwei, Vogel, Hannes, Schulder, Michael, Vakoc, Christopher R., Mills, Alea A.

Issue&Volume: 2022-12-21

Abstract: Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)—the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53 wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WT GBM. In line with these findings, BRD8 is highly expressed with H2AZ in proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WT GBM.

DOI: 10.1038/s41586-022-05551-x

Source: https://www.nature.com/articles/s41586-022-05551-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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