尽管过去几年治疗方案有了很多进步，但胃癌（GC）的五年生存率低和高复发率仍不尽人意。作为真核mRNA中最丰富的表观遗传修饰，N6-甲基腺嘌呤（m6A）甲基化参与了肿瘤进展和组织发育。在肿瘤进展中，DNA损伤修复机制可以重新编程，赋予损害基因组完整性的肿瘤克隆新的生长优势。在本研究中，我们检测到GC组织和细胞系中SUV39H2表达升高。在功能上，SUV39H2在体内外促进了GC增殖并抑制了凋亡。在机制上，METTL3介导的m6A修饰以IGF2BP2依赖方式促进了SUV39H2 mRNA的稳定性，导致SUV39H2 mRNA表达的上调。作为组蛋白甲基转移酶，SUV39H2被证实通过抑制DUSP6的转录重pression，从而增加ATM的磷酸化水平，促进HRR并最终抑制GC对顺铂的化疗敏感性。总的来说，这些结果表明m6A修饰的SUV39H2作为组蛋白甲基转移酶促进HRR以抑制GC的化疗敏感性的特定机制。SUV39H2有望成为精准治疗GC的关键目标。版权所有©2023 Elsevier B.V.。保留所有权利。

Despite many advances in treatment over the past few years, the poor 5-year survival rate and high recurrence rate of gastric cancer (GC) remain unsatisfactory. As the most abundant epigenetic modification in the eukaryotic mRNA, N6-methyladenosine (m6A) methylation participates in tumor progression and tissue development. During tumor progression, DNA damage repair mechanisms can be reprogrammed to give new growth advantages on tumor clones whose genomic integrity is disturbed. Here we detected the elevated SUV39H2 expression in GC tissues and cell lines. Functionally, SUV39H2 promoted GC proliferation and inhibited apoptosis in vitro and in vivo. Mechanistically, METTL3-mediated m6A modification promotes mRNA stability of SUV39H2 in an IGF2BP2 dependent manner, resulting in upregulated mRNA expression of SUV39H2. As a histone methyltransferase, SUV39H2 was verified to increase the phosphorylation level of ATM through transcriptional repression of DUSP6, thereby promoting HRR and ultimately inhibiting GC chemosensitivity to cisplatin. Collectively, these results indicate the specific mechanism of m6A-modified SUV39H2 as a histone methyltransferase promoting HRR to inhibit the chemosensitivity of GC. SUV39H2 is expected to become a key target in the precision targeted therapy of GC.Copyright © 2023 Elsevier B.V. All rights reserved.