Mutant p53 Confers Chemoresistance by Activating KMT5B-Mediated DNA Repair Pathway in Nasopharyngeal Carcinoma

Authors

Haidan Luo
Mo-Fan Huang
An Xu
Donghui Wang
Julian A Gingold
Jian Tu
Ruoyu Wang
Zijun Huo
Yen-Ting Chiang
Kuang-Lei Tsai
Jie Su
Danielle A Bazer
Mien-Chie Hung
Canmao Xie
Yubiao Guo
Dung-Fang Lee
Huiling Yang
Ruiying Zhao

Language

English

Publication Date

8-10-2025

Journal

Cancer Letters

DOI

10.1016/j.canlet.2025.217736

PMID

40316196

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

Humans, Tumor Suppressor Protein p53, Drug Resistance, Neoplasm, Nasopharyngeal Carcinoma, Fluorouracil, DNA Repair, Nasopharyngeal Neoplasms, Cell Line, Tumor, Animals, Mutation, Histone-Lysine N-Methyltransferase, Gene Expression Regulation, Neoplastic, Xenograft Model Antitumor Assays, Mice, Nude, Mice, DNA-Binding Proteins, Antineoplastic Combined Chemotherapy Protocols, DNA Damage

Published Open-Access

yes

Recommended Citation

Luo, Haidan; Huang, Mo-Fan; Xu, An; et al., "Mutant p53 Confers Chemoresistance by Activating KMT5B-Mediated DNA Repair Pathway in Nasopharyngeal Carcinoma" (2025). Faculty, Staff and Student Publications. 4700.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4700