KDM2A plays a dual role in regulating the expression of malignancy-related genes in esophageal squamous cell carcinoma

Biochem Biophys Res Commun. 2022 Oct 8;624:53-58. doi: 10.1016/j.bbrc.2022.07.035. Epub 2022 Jul 21.

Abstract

KDM2A is a histone demethylase, which primarily catalyzes the demethylation of H3K36me2. Abnormal expression of KDM2A is observed in many types of cancers; however, the molecular events connected to KDM2A expression remain unclear. We report that KDM2A performs an oncogenic function in esophageal squamous cell carcinoma (ESCC) and is robustly expressed in ESCC cells. ShRNA-mediated knockdown of KDM2A resulted in a significant inhibition of the malignant phenotype of ESCC cell lines, whereas ectopic expression of KDM2A showed the opposite effect. We also analyzed the function of KDM2A using a CRISPR-CAS9 depletion system and subsequent rescue experiment, which also indicated a cancerous role of KDM2A. Interestingly, analysis of the gene expression network controlled by KDM2A using RNA-seq revealed an unexpected feature: KDM2A could induce expression of a set of well-documented oncogenic genes, including IL6 and LAT2, while simultaneously suppressing another set of oncogenes, including MAT2A and HMGCS1. Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications.

Keywords: Esophageal squamous cell carcinoma; Histone marks; KDM2A; Migration; Oncogenes; Proliferation.

MeSH terms

  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation / genetics
  • Esophageal Neoplasms* / genetics
  • Esophageal Neoplasms* / pathology
  • Esophageal Squamous Cell Carcinoma* / genetics
  • F-Box Proteins* / genetics
  • F-Box Proteins* / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Methionine Adenosyltransferase / metabolism

Substances

  • F-Box Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • MAT2A protein, human
  • Methionine Adenosyltransferase