The SUMO-specific protease SENP5 controls DNA damage response and promotes tumorigenesis in hepatocellular carcinoma.

OBJECTIVE: SUMOylation plays critical roles in a variety of physiological and pathological processes including tumorigenesis. SUMOylation is a reversible process which is mediated by the SENP (Sentrin/SUMO-specific protease) family to remove SUMO from conjugated substrates. SENP5 has been reported to play critical roles in the control of several cancers including breast cancer, osteosarcoma and oral squamous cell carcinoma. In this study, we uncovered a role of SENP5 in promoting tumorigenesis process in hepatocellular carcinoma (HCC) via regulating DNA damage response.

MATERIALS AND METHODS: The mRNA and protein levels of SENP5 in 10 pairs of HCC samples were determined by Realtime PCR and Western blot, respectively. SiRNAs were used to silence the expression of SENP5 in HepG2 cells. Male BALB/c nude mice were used to determine the roles of SENP5 on tumorigenesis. In vivo SUMOylation assay was used to detect the SUMOylation of ATRIP. Immunoprecipitation (IP) was used to detect the interaction between SENP5 and ATRIP.

RESULTS: We found that SENP5 was over-expressed in HCC samples and required for HCC cells proliferation both in vitro and in vivo. SENP5-depleted HepG2 cells exhibited hypersensitivity to IR and etoposide treatment with defective checkpoint activation including decreased activation of ATR and phosphorylation of ATR targets. At the molecular level, we found that SENP5 interacted with ATRIP and promoted ATRIP deSUMOylation.

CONCLUSIONS: Overall, our data suggest that SENP5 is required for HCC cell growth and might be a promising drug target for HCC.