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Bromodomain 和 Extraterminal 结构域的过表达与进展、转移和不良结局相关：强调 BET 蛋白家族在胃癌中的预后和治疗价值。

Overexpression of Bromodomain and Extraterminal Domain is Associated with Progression, Metastasis and Unfavorable Outcomes: Highlighting Prognostic and Therapeutic Value of the BET Protein Family in Gastric Cancer.

机构信息

Hematology, Oncology and Stem Cell Transplantation Research Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

出版信息

Anticancer Agents Med Chem. 2023;23(7):794-806. doi: 10.2174/1871520623666221025145320.

DOI:10.2174/1871520623666221025145320

PMID:36284375

Abstract

BACKGROUND

As epigenetic readers, Bromodomain and extraterminal domain (BET) proteins have attracted immense interest in developing novel therapies targeting this family to inhibit cancer progression. Although the impact of BRD4 in the carcinogenesis of various tumors has been widely investigated, little is known about the potential roles of the BET family in gastric cancer.

METHODS

In this cohort study, we have screened the expression profile of the BET protein family, including three members, BRD2, BRD3 and BRD4, in fresh gastric cancer (GC), adjacent non-tumor and normal gastric tissues, as well as the anti-cancer effects and molecular mechanisms of BET inhibition in GC cell lines.

RESULTS

Among GC patients, BRD2, BRD3 and BRD4 showed overexpression, 48.07% (25/52), 61.5% (32/52) and 63.46% (33/52), respectively. The overexpression of BRD3 and BRD4 were remarkably associated with unfavorable outcomes (HR = 2.023, P = 0.038; HR = 3.874, P = 0.001, respectively). However, multivariate Cox regression analysis indicated that BRDs mRNA expression could not be used as an independent prognostic factor for GC patients after adjustment with other variables. I-BET151, a potent pan-inhibitor, suppressing the BET family, decreased cell growth, migration and invasion of GC cells. Interestingly, I-BET151 induced G1 cell cycle arrest through down-regulation of c-Myc and its target, CDK2/Cyclin D1 complex.

CONCLUSIONS

Our data provide insights into the prognostic role of the BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.

摘要

背景

作为表观遗传读码器，Bromodomain 和 extraterminal 结构域（BET）蛋白已成为靶向该家族开发新型治疗方法以抑制癌症进展的热点。尽管 BRD4 在各种肿瘤的致癌作用已被广泛研究，但 BET 家族在胃癌中的潜在作用知之甚少。

方法

在本队列研究中，我们筛选了 BET 蛋白家族（包括 BRD2、BRD3 和 BRD4 三个成员）在新鲜胃癌（GC）、癌旁非肿瘤和正常胃组织中的表达谱，以及 BET 抑制在 GC 细胞系中的抗癌作用和分子机制。

结果

在 GC 患者中，BRD2、BRD3 和 BRD4 的过表达率分别为 48.07%（25/52）、61.5%（32/52）和 63.46%（33/52）。BRD3 和 BRD4 的过表达与不良结局显著相关（HR=2.023，P=0.038；HR=3.874，P=0.001）。然而，多变量 Cox 回归分析表明，在调整其他变量后，BRDmRNA 表达不能作为 GC 患者的独立预后因素。I-BET151 是一种强效的泛 BET 抑制剂，可抑制 BET 家族，降低 GC 细胞的生长、迁移和侵袭能力。有趣的是，I-BET151 通过下调 c-Myc 及其靶标 CDK2/Cyclin D1 复合物诱导 G1 细胞周期停滞。