USP11 promotes glycolysis by regulating HIF‐1α stability in hepatocellular carcinoma

Abstract Understanding the mechanisms underlying metastasis in hepatocellular carcinoma (HCC) is crucial for developing new therapies against this fatal disease. Deubiquitinase ubiquitin‐specific protease 11 (USP11) belongs to the deubiquitinating family and has previously been reported to play a critical role in cancer pathogenesis. Although it has been established that USP11 can facilitate the metastasis and proliferation ability of HCC, the underlying regulatory mechanisms are poorly understood. The primary objective of this research was to reveal hitherto undocumented functions of USP11 during HCC progression, especially those related to metabolism. Under hypoxic conditions, USP11 was found to significantly impact the glycolysis of HCC cells, as demonstrated through various techniques, including RNA‐Seq, migration and colony formation assays, EdU and co‐immunoprecipitation. Interestingly, we found that USP11 interacted with the HIF‐1α complex and maintained HIF‐1α protein stability by removing ubiquitin. Moreover, USP11/HIF‐1α could promote glycolysis through the PDK1 and LDHA pathways. In general, our results demonstrate that USP11 promotes HCC proliferation and metastasis through HIF‐1α/LDHA‐induced glycolysis, providing new insights and the experimental basis for developing new treatments for this patient population.