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

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-03-03 DOI:10.1016/j.lfs.2025.123527

Shuo Chen , Jing-Tao Wen , Song Zhang , Jie-Lin Wang , Jing Yuan , Hai-Juan Bao , Xi Chen , Yang Zhao

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Abstract

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.

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SNORD9通过METTL3/ igf2bp2介导的NFYA m6A修饰促进卵巢癌的肿瘤发生，是反义寡核苷酸治疗的潜在靶点

已知C/D盒小核仁非编码rna （small nucleolar noncoding rna, snoRNAs）结合并诱导rna的2 ' - o -核糖甲基化，参与肿瘤的发生和发展。然而，它们参与调节m6A的修饰仍未被报道。对TCGA数据库的分析显示，SNORD9是卵巢癌的不利预后因素。此外，SNORD9在卵巢癌中升高。在体外，SNORD9过表达诱导卵巢癌细胞增殖和迁移，在体内诱导致瘤性，通过与m6A甲基转移酶METTL3结合，提高m6A修饰水平，影响NFYA m6A修饰；此外，m6A-reader IGF2BP2被SNORD9 2 ' - o甲基化，从而影响NFYA mRNA的稳定性，上调NFYA及其下游蛋白CCND1、CDK4和VEGFA，促进卵巢癌的肿瘤发生。aso介导的SNORD9沉默在体外和体内均抑制了致瘤性，并有效抑制了卵巢癌患者源性类器官（OC-PDO）的生长。总之，我们首次证明了SNORD9通过结合m6A甲基化酶METTL3诱导NFYA m6A甲基化；通过2′- o甲基化修饰IGF2BP2 mRNA，提高NFYA mRNA的稳定性，从而促进卵巢癌的肿瘤发生。ASO靶向治疗SNORD9可能具有治疗卵巢癌的疗效。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.