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SNORD9 promotes ovarian cancer tumorigenesis via METTL3/IGF2BP2-mediated NFYA m6A modification and is a potential
Shuo Chen1, Jing-Tao Wen1, Song Zhang2
1Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office; Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
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.
Insights
Small nucleolar RNA SNORD9 promotes ovarian cancer by increasing N6-methyladenosine (m6A) modification. Silencing SNORD9 inhibits tumor growth, suggesting it as a therapeutic target for ovarian cancer.
Area of Science:
- Molecular Biology
- Oncology
- RNA Biology
Background:
- C/D box small nucleolar noncoding RNAs (snoRNAs) are involved in RNA methylation and cancer development.
- The role of snoRNAs in regulating N6-methyladenosine (m6A) modification is largely unknown.
- SNORD9 is implicated as a potential factor in ovarian cancer progression.
Purpose of the Study:
- To investigate the role of SNORD9 in ovarian cancer.
- To elucidate the mechanism by which SNORD9 affects m6A modification and tumorigenesis.
- To evaluate SNORD9 as a potential therapeutic target in ovarian cancer.
Main Methods:
- TCGA database analysis to assess SNORD9 expression and prognostic value.
- In vitro and in vivo experiments to study the effects of SNORD9 overexpression and silencing.
- Mechanism studies involving METTL3, IGF2BP2, and NFYA interactions.
- Assessment of SNORD9 inhibition using antisense oligonucleotides (ASOs) in cell lines and patient-derived organoids.
Main Results:
- SNORD9 is upregulated in ovarian cancer and serves as an unfavorable prognostic factor.
- Overexpression of SNORD9 promotes ovarian cancer cell proliferation, migration, and tumorigenicity.
- SNORD9 binds to METTL3, affecting NFYA m6A modification and IGF2BP2 2'-O-methylation, leading to increased NFYA mRNA stability.
- Silencing SNORD9 with ASOs suppresses tumor growth in vitro, in vivo, and in ovarian cancer patient-derived organoids.
Conclusions:
- SNORD9 promotes ovarian cancer tumorigenesis by enhancing NFYA m6A methylation via METTL3 and increasing NFYA mRNA stability through IGF2BP2 modification.
- Targeting SNORD9 with ASOs represents a potential therapeutic strategy for ovarian cancer treatment.
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