N6-methyadenosine modified SUV39H2 regulates homologous recombination through epigenetic repression of DUSP6 in gastric cancer

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.

DSBs; Gastric cancer; Homologous recombination; SUV39H2; m(6)A modification.