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

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. (C) 2022 Elsevier Inc. All rights reserved.

Automated summary

The histone demethylase KDM2A plays an oncogenic role in esophageal squamous cell carcinoma, with its depletion inhibiting malignant phenotypes and overexpression having the opposite effect. KDM2A induces a set of oncogenic gene expressions while suppressing others, demonstrating its dual role in ESCC cells. Targeted inhibition of upregulated oncogenes in KDM2A-depleted cells shows a synergistic suppressive effect on ESCC malignant phenotypes.