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

Yang Chen, Yin Zhao, Xiaojing Yang, Xianyue Ren, Shengyan Huang, Sha Gong, Xirong Tan, Junyan Li, Shiwei He, Yingqin Li, Xiaohong Hong, Qian Li, Cong Ding, Xueliang Fang, Jun Ma and Na Liu ()
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Yang Chen: Sun Yat-sen University Cancer Center
Yin Zhao: Sun Yat-sen University Cancer Center
Xiaojing Yang: Sun Yat-sen University Cancer Center
Xianyue Ren: Sun Yat-sen University
Shengyan Huang: Sun Yat-sen University Cancer Center
Sha Gong: Sun Yat-sen University Cancer Center
Xirong Tan: Sun Yat-sen University Cancer Center
Junyan Li: Sun Yat-sen University Cancer Center
Shiwei He: Sun Yat-sen University Cancer Center
Yingqin Li: Sun Yat-sen University Cancer Center
Xiaohong Hong: Sun Yat-sen University Cancer Center
Qian Li: Sun Yat-sen University Cancer Center
Cong Ding: Sun Yat-sen University Cancer Center
Xueliang Fang: Sun Yat-sen University Cancer Center
Jun Ma: Sun Yat-sen University Cancer Center
Na Liu: Sun Yat-sen University Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28158-2

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