PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma

Sheng-Yan Huang, Sha Gong, Yin Zhao, Ming-Liang Ye, Jun-Yan Li, Qing-Mei He, Han Qiao, Xi-Rong Tan, Jing-Yun Wang, Ye-Lin Liang, Sai-Wei Huang, Shi-Wei He, Ying-Qin Li, Sha Xu, Ying-Qing Li () and Na Liu ()
Additional contact information
Sheng-Yan Huang: Sun Yat-sen University Cancer Center
Sha Gong: Sun Yat-sen University Cancer Center
Yin Zhao: Sun Yat-sen University Cancer Center
Ming-Liang Ye: Sun Yat-sen University Cancer Center
Jun-Yan Li: Sun Yat-sen University Cancer Center
Qing-Mei He: Sun Yat-sen University Cancer Center
Han Qiao: Sun Yat-sen University Cancer Center
Xi-Rong Tan: Sun Yat-sen University Cancer Center
Jing-Yun Wang: Sun Yat-sen University Cancer Center
Ye-Lin Liang: Sun Yat-sen University Cancer Center
Sai-Wei Huang: Sun Yat-sen University Cancer Center
Shi-Wei He: Sun Yat-sen University Cancer Center
Ying-Qin Li: Sun Yat-sen University Cancer Center
Sha Xu: Sun Yat-sen University Cancer Center
Ying-Qing Li: Sun Yat-sen University Cancer Center
Na Liu: Sun Yat-sen University Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.

Date: 2024
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DOI: 10.1038/s41467-024-49675-2

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