USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Abstract Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers therapy with multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α activated its activity subsequent induction promote Sorafenib HCC. Here, we report ubiquitin-specific peptidase USP29 as a new regulator during development particular, identified critical deubiquitylase (DUB) HIF1α, which directly deubiquitylates stabilizes and, thus, promotes transcriptional activity. Among targets gene encoding hexokinase 2 (HK2), key enzyme glycolytic pathway. The absence USP29, thus activity, reduces levels restores sensitivity Sorafenib-resistant HCC cells vitro xenograft transplantation mouse models vivo. Notably, high HK2 correlate response patients therapy. Together, data demonstrate that, DUB cells, parts by upregulating glycolysis, thereby opening avenues for therapeutically targeting patients.