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

J Cell Mol Med. 2024 Jun;28(12):e18500. doi: 10.1111/jcmm.18500.

Abstract

Eukaryotic cells possess multiple mechanisms of self-destruction, including pyroptosis and necroptosis. Pyroptosis is a type of programmed cell death characterized by cellular rupture and linked to inflammation. SnoRNA, a small non-coding RNA in the nucleolus, can dysregulate specific RNAs through 2'-O-methylation, contributing to tumorigenesis. Our StarBase and qRT-PCR analysis revealed SNORD99 upregulation in endometrial cancer (EC) tissue compared to normal tissue, suggesting its role in pathogenesis. SNORD99 overexpression enhanced migration and proliferation of EC cells, while ASO-mediated suppression reduced malignant cell spread and division. RNA-seq and base-comparing analysis identified GSDMD's differential expression upon SNORD99 overexpression, forming the SNORD99-FBL RNP complex. RTL-P experiments showed SNORD99 increased GSDMD's 2'-O-methylation. SNORD99 reduced GSDMD, caspase-1, and NLRP3 protein levels, implicating its role in pyroptosis. Optical and electron microscopy confirmed enhanced pyroptosis features. In summary, SNORD99 modifies GSDMD via 2'-O-methylation, suppressing pyroptosis and promoting EC progression. Developing pyroptosis-inducing drugs may offer new cancer treatment avenues.

Keywords: 2'‐O‐methylation; GSDMD; endometrial cancer; pyroptosis; small nucleolar RNA.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation*
  • Endometrial Neoplasms* / genetics
  • Endometrial Neoplasms* / metabolism
  • Endometrial Neoplasms* / pathology
  • Female
  • Gasdermins
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Methylation
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / metabolism
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • Pyroptosis* / genetics
  • Ribonucleoproteins, Small Nucleolar / genetics
  • Ribonucleoproteins, Small Nucleolar / metabolism

Substances

  • GSDMD protein, human
  • Intracellular Signaling Peptides and Proteins
  • Ribonucleoproteins, Small Nucleolar
  • Phosphate-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Gasdermins