Transcription factor ONECUT3 regulates HDAC6/HIF-1α activity to promote the Warburg effect and tumor growth in colorectal cancer.

The Warburg effect, also known as aerobic glycolysis, plays a crucial role in the onset and progression of colorectal cancer (CRC), although its mechanism remains unclear. In this study, bioinformatics analysis of public databases combined with validation using clinical specimens identified the transcription factor ONECUT3 as a key regulator related to the Warburg effect in CRC. Functionally, silencing ONECUT3 reverses the Warburg effect and suppresses tumor growth. Importantly, ONECUT3 promotes tumor growth in a glycolysis-dependent manner through hypoxia-inducible factor 1α (HIF-1α). Mechanistically, ONECUT3 does not directly regulate the expression of HIF-1α but instead inhibits its acetylation via histone deacetylase 6 (HDAC6). This deacetylation enhances the transcriptional activity of HIF-1α, ultimately upregulating multiple glycolysis-related genes downstream of HIF-1α, thereby driving the Warburg effect and facilitating tumor growth in CRC. These findings reveal a novel mechanism by which ONECUT3 regulates the Warburg effect in CRC and suggest that targeting ONECUT3 may offer a promising therapeutic strategy for CRC.