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Overexpression of bromodomain and extraterminal domain is associated with progression, metastasis and unfavorable outcome: highlighting prognostic and therapeutic value of BET protein family in gastric cancer

Background and objective: Bromodomain and extraterminal domain (BET) proteins as epigenetic readers have attracted immense interest for 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 BET family in gastric cancer.

Methods: In this cohort study, we have screened the expression profile of 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. Overexpression of BRD3 and BRD4 were remarkably associated with unfavorable outcome (HR=2.023, P=0.038; HR=3.874, P=0.001 respectively). However, multivariate Cox regression analysis indicated that BRDs mRNA expression cannot be used as independent prognostic factors for GC patients after adjustment with other variables. Suppression of BET family, using I-BET151, a potent pan-inhibitor 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 BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.