Mutant p53 confers chemoresistance by activating KMT5B-mediated DNA repair pathway in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC), a malignancy arising from the nasopharyngeal epithelium, is common in the east and southeast area of Asia. Treatments for locally advanced and recurrent NPC include chemotherapy (usually combined with 5-Fluorouracil, 5-FU) and radiotherapy, but response is limited due to chemo-resistance. p53 mutation is a critical factor for 5-FU resistance in some cancers, but its role in NPC chemo-resistance remains unclear. Here, we demonstrate that p53(R280T), a common p53 somatic mutation found in multiple NPC tumor samples, induces gain-of-function upregulation of DNA repair genes which leads to 5-FU resistance in NPC. p53(R280T) specifically upregulates the expression of DNA repair-associated gene KMT5B by binding to its promoter, which leads to 5-FU resistance. Depletion of KMT5B in NPCs restores 5-FU induced DNA damages and improve the efficacy of 5-FU. By screening compounds affecting KMT5B expression, we identify curcumin as an effective down-regulator of KMT5B in NPC cells. We therefore evaluate the therapeutic potential of a 5-FU/curcumin combination to treat NPC and discover that curcumin enhances the efficacy of 5-FU to suppress NPC tumor growth. In summary, our findings indicate that mutant p53 and its regulated DNA repair genes serve as potential therapeutic targets to reverse 5-FU resistance for NPC patients.

Keywords: 5-FU; Chemoresistance; Curcumin; DNA repair; KMT5B; Mutant p53; Nasopharyngeal carcinoma.