Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Biochem Pharmacol. 2023 Dec;218:115877. doi: 10.1016/j.bcp.2023.115877. Epub 2023 Oct 23.
Colorectal carcinoma (CRC), one of the most life-threatening cancer types, is associated with aberrant expression of epigenetic modifiers and activation of the Wnt pathway. However, the role of epigenetic regulators in driving cancer cell proliferation and their potential as therapeutic targets affecting the Wnt pathway remain unclear. In this study, BRD4 was found to promote the progression of CRC both in vitro and in vivo. The expression of BRD4 correlated with shortened CRC patient survival. In addition, BRD4 function was strongly correlated with the Wnt pathway, but rather through regulation of TCF7L2 at transcriptional levels. BRD4 and H3K27ac have overlapping occupancies in the cis-regulatory elements of TCF7L2, suggesting enhancer-based epigenetic regulation. Numerous YY1 binding sites were found in the abovementioned region. YY1 recruited BRD4 to bind to cis-regulatory elements of TCF7L2, thereby regulating the expression of TCF7L2. Altogether, this study validates that BRD4 performs a canonical epigenetic regulatory function in CRC and can be used in the treatment of Wnt pathway-dependent CRC or other malignancies with clinically available bromodomain inhibitors.
结直肠癌（CRC）是最具威胁生命的癌症类型之一，与表观遗传修饰物的异常表达和 Wnt 通路的激活有关。然而，表观遗传调节剂在驱动癌细胞增殖中的作用及其作为影响 Wnt 通路的治疗靶点的潜力仍不清楚。在这项研究中，发现 BRD4 可促进 CRC 在体外和体内的进展。BRD4 的表达与 CRC 患者生存时间缩短相关。此外，BRD4 功能与 Wnt 通路密切相关，但主要是通过转录水平调节 TCF7L2。BRD4 和 H3K27ac 在 TCF7L2 的顺式调控元件中具有重叠的占有率，提示存在基于增强子的表观遗传调控。在上述区域发现了许多 YY1 结合位点。YY1 将 BRD4 募集到 TCF7L2 的顺式调控元件，从而调节 TCF7L2 的表达。总的来说，这项研究证实 BRD4 在 CRC 中发挥了典型的表观遗传调控功能，并且可以使用临床上可用的溴结构域抑制剂治疗依赖 Wnt 通路的 CRC 或其他具有潜在治疗价值的恶性肿瘤。
