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

Abstract The Warburg effect, also known as aerobic glycolysis, plays a crucial role in the onset and progression of colorectal cancer, although its mechanism remains unclear. Bioinformatics analysis of public databases and verification of clinical specimens revealed that the transcription factor ONECUT3 is a key regulator related to the Warburg effect in colorectal cancer. Functionally, genetic silencing of ONECUT3 reverses the Warburg effect and blunts tumor growth. Importantly, ONECUT3 promotes tumor growth in a glycolysis-dependent manner. Mechanistically, ONECUT3 does not directly alter the expression of hypoxia-inducible factor 1α (HIF-1α), but rather inhibits the acetylation of HIF-1α via histone deacetylase 6 (HDAC6). This inhibition leads to increased transcriptional activity of HIF-1α, ultimately upregulating various glycolysis-related genes downstream of HIF-1α, thereby promoting the Warburg effect in colorectal cancer and facilitating tumor growth. Our study provides evidence for the mechanism of the Warburg effect in colorectal cancer, suggesting that ONECUT3 could be a potential new target for colorectal cancer treatment.