胃癌（GC）是全球第五大常见癌症，也是全球第二大癌症死亡原因。 SETD2 是一种组蛋白甲基转移酶，可催化 H3K36 (H3K36me3) 三甲基化，并已被证明参与多种生物过程和人类肿瘤。然而，SETD2在GC中的作用机制仍不清楚。在此，我们报道 Setd2 缺陷预示着胃癌的不良预后。 SETD2 缺失分别促进了 H. felis/MNU 和 c-Myc 诱导的胃肿瘤发生。胃特异性 Setd2 缺失和 c-MYC 过度表达 (AMS) 的小鼠模型仅在 10-12 周龄时就出现了高度上皮缺陷、肠化生和发育不良。从机制上讲，Setd2 缺失会导致 Sirt1 表观遗传调控受损，从而抑制 SIRT1/FOXO 通路。此外，FOXO信号传导的激动剂或SIRT1的过表达显着挽救了SGC7901细胞中Setd2缺陷引起的细胞增殖和迁移增强。总之，我们的研究结果强调了 SETD2 通过 SIRT1/FOXO 途径调节胃肿瘤发生的表观遗传机制。它还可能为针对 Setd2 缺陷的 GC 患者开发针对患者的针对性疗法铺平道路。版权所有 © 2023。由 Elsevier B.V. 出版。

Gastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer death globally. SETD2 is a histone methyltransferase catalyzing tri-methylation of H3K36 (H3K36me3) and has been shown to participate in diverse biological processes and human tumors. However, the mechanism of SETD2 in GC remains unclear. Here, we reported that Setd2 deficiency predicts poor prognosis of gastric cancer. SETD2 loss facilitated H. felis/MNU and c-Myc-induced gastric tumorigenesis, respectively. The mouse model of stomach-specific Setd2 depletion together with c-MYC overexpression (AMS) developed high-grade epithelial defects, intestinal metaplasia and dysplasia at only 10-12 weeks of age. Mechanistically, Setd2 depletion resulted in impaired epigenetic regulation of Sirt1, thus inhibiting the SIRT1/FOXO pathway. Moreover, the agonists of FOXO signaling or overexpression of SIRT1 significantly rescued the enhanced cell proliferation and migration caused by Setd2 deficiency in SGC7901 cells. Together, our findings highlight an epigenetic mechanism by which SETD2 regulates gastric tumorigenesis through SIRT1/FOXO pathway. It may also pave the way for the development of targeted, patient-tailored therapies for GC patients with Setd2 deficiency.Copyright © 2023. Published by Elsevier B.V.