ETS Variant Transcription Factor 6 Promotes Glucose Metabolism Reprogramming in HCC

ABSTRACT Glucose metabolic reprogramming is a key hallmark of tumour cells, and the designed inhibitors targeting tumour glucose metabolism reprogramming may serve as an effective therapeutic strategy. The ETS Variant Transcription Factor 6 (ETV6) is a potent transcriptional repressor strongly associated with tumorgenesis. However, the precise role and underlying action mechanism of ETV6 in tumour glucose metabolism reprogramming remain unreported. In this study, we demonstrate that the ETV6‐miR‐429‐CRKL regulatory axis contributes to metabolism reprogramming in HCC. Overexpression or knockdown of ETV6 and CRKL enhances or inhibits the Warburg effect and glycogen synthesis in HCC cells both in vitro and in vivo. In contrast, miR‐429 overexpression and knockdown exert opposing effects on the Warburg effect compared to the overexpression and knockdown of ETV6 and CRKL. Moreover, miR‐429 regulates the rate of glycogen production and degradation by enhancing the activities of GCS and GPa to promote glycogen synthesis, subsequently coupling with the aerobic glycolytic pathway by mediating glycogen shunting. Mechanistically, ETV6 binds to the miR‐429 promoter, mediating glucose metabolic reprogramming in HCC cells by targeting CRKL via the PI3K/AKT pathway. Taken together, these findings reveal that the ETV6‐miR‐429‐CRKL regulatory circuitry plays a crucial role in glucose metabolic reprogramming in HCC, offering novel insight and a potential target for cancer therapy.