Yang Jing, Xu Penghui, Chen Zetian, Zhang Xing, Xia Yiwen, Fang Lang, Xie Li, Li Bowen, Xu Zekuan
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, China.
Cancer Lett. 2023 Apr 1;558:216092. doi: 10.1016/j.canlet.2023.216092. Epub 2023 Feb 15.
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 (mA) 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 mA 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 mA-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.
尽管在过去几年治疗方面取得了许多进展，但胃癌（GC）令人不满意的5年生存率和高复发率仍然存在。作为真核生物mRNA中最丰富的表观遗传修饰，N6-甲基腺苷（m⁶A）甲基化参与肿瘤进展和组织发育。在肿瘤进展过程中，DNA损伤修复机制可被重新编程，从而赋予基因组完整性受到干扰的肿瘤克隆新的生长优势。在此，我们检测到GC组织和细胞系中SUV39H2表达升高。在功能上，SUV39H2在体外和体内均促进GC增殖并抑制细胞凋亡。机制上，METTL3介导的m⁶A修饰以IGF2BP2依赖的方式促进SUV39H2的mRNA稳定性，导致SUV39H2的mRNA表达上调。作为一种组蛋白甲基转移酶，SUV39H2通过对DUSP6的转录抑制被证实可增加ATM的磷酸化水平，从而促进同源重组修复（HRR）并最终抑制GC对顺铂的化疗敏感性。总体而言，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化疗敏感性的具体机制。SUV39H2有望成为GC精准靶向治疗的关键靶点。
