KDM1A promotes colorectal cancer growth by regulating the HIF-1α/PDK4-mediated glycolysis.

Abstract

This study elucidated the mechanism by which lysine-specific demethylase 1 A (KDM1A) promotes colorectal cancer (CRC) progression. We characterized KDM1A expression in CRC cells and tissues and examined its effects on malignant phenotypes, including proliferation, migration, invasion, and glycolysis. Mechanistically, we explored the relationship between KDM1A and hypoxia-inducible factor-1α (HIF-1α)/PDK4 pathway. The tumor-promoting role of KDM1A was further evaluated in a xenograft mouse model. The results showed that KDM1A was overexpressed in CRC cells and tissues. KDM1A knockdown inhibited CRC cell proliferation, migration, and invasion capabilities, and reduced glycolytic activity. Furthermore, KDM1A knockdown shortened the half-life of HIF-1α protein and increased its ubiquitination level, correlating with reduced PDK4 expression. HIF-1α overexpression partially reversed the PDK4 downregulation and glycolysis inhibition caused by KDM1A knockdown. PDK4 knockdown reproduced the metabolic inhibition phenotype of KDM1A deficiency, and KDM1A overexpression reversed the effects of PDK4 deficiency, confirming that KDM1A regulates glycolysis in a PDK4-dependent manner. KDM1A depletion suppressed in vivo tumor growth and decreased Ki-67 and HIF-1α expression levels. In conclusion, KDM1A supports PDK4 expression via HIF-1α stability, promoting glycolytic metabolism and driving CRC growth and metastasis.