Journal Article

USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma

Zhao, Yin, Chen, Yang, Ren, Xianyue, He, Shiwei, Hong, Xiaohong, Li, Qian, Fang, Xueliang, Li, Junyan, Tan, Xirong, Liu, Na, Ding, Cong, Ma, Jun, Yang, Xiaojing, Huang, Shengyan, Gong, Sha, Li, Yingqin

2022

Overview

Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC), and approximately 20% of patients experience treatment failure due to tumour radioresistance. However, the exact regulatory mechanism remains poorly understood. Here, we show that the deubiquitinase USP44 is hypermethylated in NPC, which results in its downregulation. USP44 enhances the sensitivity of NPC cells to radiotherapy in vitro and in vivo. USP44 recruits and stabilizes the E3 ubiquitin ligase TRIM25 by removing its K48-linked polyubiquitin chains at Lys439, which further facilitates the degradation of Ku80 and inhibits its recruitment to DNA double-strand breaks (DSBs), thus enhancing DNA damage and inhibiting DNA repair via non-homologous end joining (NHEJ). Knockout of TRIM25 reverses the radiotherapy sensitization effect of USP44. Clinically, low expression of USP44 indicates a poor prognosis and facilitates tumour relapse in NPC patients. This study suggests the USP44-TRIM25-Ku80 axis provides potential therapeutic targets for NPC patients. Radiotherapy is the mainstay treatment for nasopharyngeal carcinoma (NPC). Here the authors show that the deubiquitinase, USP44, increases radiosensitivity of NPC cells by promoting the degradation of Ku80, and thus enhancing the levels of DNA damage.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 13/109 / 13/2 / 13/31 / 13/51 / 14/19 / 140/58 / 38/88 / 38/89 / 45/22 / 631/337/176/1988 / 631/67/1059/485 / 631/67/1244 / 631/67/1536 / Apoptosis - genetics / Apoptosis - radiation effects / Cancer / Carcinogenesis - genetics / Carcinogenesis - metabolism / Cell Line / Cell Line, Tumor / Damage / Degradation / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded - radiation effects / DNA damage / DNA Methylation / DNA repair / DNA Repair - genetics / Double-strand break repair / G2 Phase Cell Cycle Checkpoints - genetics / G2 Phase Cell Cycle Checkpoints - radiation effects / Gene Expression Regulation, Neoplastic / HEK293 Cells / Homology / Humanities and Social Sciences / Humans / Irradiation / Ku Autoantigen - genetics / Ku Autoantigen - metabolism / multidisciplinary / Nasopharyngeal carcinoma / Nasopharyngeal Carcinoma - genetics / Nasopharyngeal Carcinoma - metabolism / Nasopharyngeal Carcinoma - pathology / Nasopharyngeal Neoplasms - genetics / Nasopharyngeal Neoplasms - metabolism / Nasopharyngeal Neoplasms - pathology / Non-homologous end joining / Patients / Promoter Regions, Genetic - genetics / Radiation therapy / Radiation Tolerance - genetics / Radioresistance / Radiosensitivity / Regulatory mechanisms (biology) / Repair / Science / Science (multidisciplinary) / Sensitivity enhancement / Survival Analysis / Therapeutic targets / Throat cancer / Transcription Factors - genetics / Transcription Factors - metabolism / Tripartite Motif Proteins - genetics / Tripartite Motif Proteins - metabolism / Tumorigenesis / Tumors / Ubiquitin / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - metabolism / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Ubiquitination / Yeast