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.
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