SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop

Objective We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness. Design HCC cancer stemness was analysed by selfrenewal ability, chemoresistance, expression of stemnessrelated genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed. Results We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1 alpha deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1 alpha. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2 alpha and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1 alpha. Conclusions Taken together, our findings suggest the significance of this positive feedback loop between HIF1 alpha and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.