SNORD99 promotes endometrial cancer development by inhibiting GSDMD-mediated pyroptosis through 2'-O-methylation

Jing-Yuan Xian1,2, Wu Wu1,2, Xi Chen1,2

  • 1Department of Obstetrics and Gynecology, 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 of Guangzhou Medical University, Guangzhou, China.

Insights

SNORD99, a small nucleolar RNA, promotes endometrial cancer by suppressing pyroptosis. It methylates GSDMD, inhibiting cell death and enhancing tumor growth, suggesting new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Eukaryotic cells have self-destruction mechanisms like pyroptosis.
  • Small nucleolar RNAs (snoRNAs) can regulate gene expression and are implicated in cancer.
  • Pyroptosis is a pro-inflammatory programmed cell death pathway crucial in immunity and disease.

Purpose of the Study:

  • To investigate the role of SNORD99 in endometrial cancer (EC) pathogenesis.
  • To elucidate the molecular mechanism by which SNORD99 influences cell death pathways.
  • To explore SNORD99 as a potential therapeutic target for EC.

Main Methods:

  • StarBase and qRT-PCR for SNORD99 expression analysis in EC tissues.
  • Cell proliferation, migration assays, and ASO-mediated knockdown in EC cells.
  • RNA-sequencing, RNP complex formation analysis, RTL-P, Western blotting, and microscopy to study SNORD99-GSDMD interaction and pyroptosis.

Main Results:

  • SNORD99 was significantly upregulated in EC tissues and promoted EC cell migration and proliferation.
  • SNORD99 overexpression led to the formation of a SNORD99-FBL RNP complex and increased GSDMD 2'-O-methylation.
  • SNORD99 suppressed pyroptosis by reducing GSDMD, caspase-1, and NLRP3 protein levels, thereby promoting EC progression.

Conclusions:

  • SNORD99 promotes endometrial cancer progression by inhibiting pyroptosis through GSDMD 2'-O-methylation.
  • Targeting SNORD99 or enhancing pyroptosis could be a viable therapeutic strategy for EC.
  • This study reveals a novel mechanism linking snoRNAs to cell death regulation in cancer.

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