SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair

BackgroundCisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy.ResultsWe performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locus SETD8 (7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization after SETD8 downregulation. Knockdown of SETD8 increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition, SETD8 expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor of SETD8 was found to enhance cisplatin sensitivity both in vitro and in vivo.ConclusionsSETD8 was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy.

Automated summary

SETD8 mutation is frequently associated with cisplatin resistance in cervical cancer. Knockdown of SETD8 increases cervical cancer cell sensitivity to cisplatin by reducing 53BP1 binding to DNA breaks and inhibiting the non-homologous end joining repair pathway. Furthermore, SETD8 expression is correlated with cisplatin resistance and poor prognosis in cervical cancer patients. The small molecule inhibitor UNC0379 enhances cisplatin sensitivity in vitro and in vivo.