Sentrin/SUMO-specific protease 1 contributes to drug resistance in melanoma by mediating the deSUMOylation of Yes-associated protein.

Abstract

Introduction: The effectiveness of chemotherapy in treating melanoma is limited due to drug resistance. Previous studies have shown that SENP1 (Sentrin/SUMO-specific protease 1) is related to the tumour hypoxic microenvironment, tumorigenesis and metastasis.

Aim: This study aimed to investigate its roles in drug resistance of melanoma.

Material and methods: Originally, a concentration of 2 μg/ml dacarbazine (DTIC) was employed in the treatment of A375 and M14 cell lines for a duration of 24 h. Subsequently, the cells were transferred to fresh medium and allowed to proliferate until reaching 80% of their maximum density. This treatment cycle was then repeated for a total of 10 days, following which the DTIC concentration was doubled. The establishment of drug-resistant cell lines for both A375 and M14 occurred after 8 months of sustained and continuous treatment. The expression level of SENP1 was monitored monthly using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), with a fold change above 1.5 compared to the untreated condition considered as significant.

Results: Finally, the study found that SENP1 was up-regulated by about 2.2-1.7 times in the drug-resistant cells. In addition, overexpression of SENP1 in normal A375 cells improved cell viability against DTIC. The study also found that Yes-associated protein (YAP) could form protein condensates in the cytoplasm while its expression was enhanced by SENP1-mediated deSUMOylation.

Conclusions: This study suggests that there is a positive correlation between the ubiquitin-specific protease SENP1 and drug resistance in melanoma. Its up-regulation may lead to changes in the deSUMOylation of YAP, activate the Hippo signalling pathway, and increase the resistance of melanoma to DTIC.