SNORD9 promotes ovarian cancer tumorigenesis via METTL3/IGF2BP2-mediated NFYA m6A modification and is a potential target for antisense oligonucleotide therapy.

C/D box small nucleolar noncoding RNAs (snoRNAs) are known to bind and induce 2'-O-ribose methylation of RNAs, participate in cancer tumorigenesis and development. However, their involvement in regulating m6A modification remains unreported. Analysis of the TCGA database revealed that SNORD9 was an unfavorable prognostic factor for ovarian cancer. Besides, SNORD9 was elevated in ovarian cancer. The overexpression of SNORD9 induced ovarian cancer cell proliferation and migration in vitro and induce tumorigenicity in vivo, increased the m6A modification level by binding to m6A-methyltransferase METTL3 to affect NFYA m6A modification; besides, m6A-reader IGF2BP2 was 2'-O-methylated by SNORD9, thereby affect NFYA mRNA stability, upregulate NFYA and its downstream proteins CCND1, CDK4 and VEGFA, promote ovarian cancer tumorigenesis. ASO-mediated silencing of SNORD9 suppressed tumorigenicity both in vitro and in vivo, and effectively inhibited the growth of patient-derived organoids of ovarian cancer (OC-PDO). In conclusions, we demonstrated for the first time that SNORD9 induces NFYA m6A methylation by binding to m6A methylase METTL3; modifying IGF2BP2 mRNA by 2'-O-methylation and improve NFYA mRNA stability, thus promote the tumorigenesis of ovarian cancer. Targeting ASO to SNORD9 may have efficacy in the treatment of ovarian cancer.