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

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 alpha (HIF1 alpha) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1 alpha is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1 alpha and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1 alpha, which directly deubiquitylates and stabilizes HIF1 alpha and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1 alpha is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1 alpha transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1 alpha, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

Automated summary

The study identifies USP29 as a regulator of HIF1α and aerobic glycolysis during Sorafenib resistance development in hepatocellular carcinoma. USP29 stabilizes HIF1α transcriptional activity by deubiquitylating, leading to upregulation of glycolytic pathway enzyme HK2, and promoting resistance to Sorafenib in HCC cells. The absence of USP29 restores sensitivity to Sorafenib and correlates with patient response to therapy, suggesting a potential therapeutic target for Sorafenib-resistant HCC.