Wang Xuecen, Cao Zhirui, Yue Xin, Liu Tingyu, Wen Gesi, Jiang Dongmei, Wu Weijian, Le Liyuan, Wang Yan, Wang Chengtao, Wang Ziyang, Jin Meng, Zhu Meiyan, He Shasha, Zhang Xiaoyue, Bu Xianzhang, Liu Ran-Yi, Peng Zhenwei, Chen Yong
Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Mol Ther Oncolytics. 2022 Aug 5;26:330-346. doi: 10.1016/j.omto.2022.08.002. eCollection 2022 Sep 15.
The use of radiotherapy for hypopharyngeal cancer (HC) treatment is increasing, and it is currently the primary treatment option for this cancer. However, radioresistance occurs in a proportion of patients. Here, we found that radiation increased proteasomal gene expression and that proteasome assembly was dependent on the induction of transcription factor NRF1 in HC. Through screening assays, we identified a mechanism by which proteasome-mediated degradation of DEP domain-containing mTOR-interacting protein (DEPTOR) contributes to the elevation of mTORC1 signaling after radiation. Therefore, after treatment with proteasome inhibitors (PIs), stabilization of DEPTOR inhibited mTORC1 signaling elevated by radiation and ultimately sensitized HC to radiotherapy. Mechanically, PIs not only interrupted the deubiquitination and degradation of DEPTOR but also suppressed the ubiquitination of DEPTOR mediated by β-TrCP. Clinically, the high levels of DEPTOR in HC cells were associated with sensitivity to radiotherapy and favorable prognosis. Stabilizing DEPTOR through targeting proteasome-mediated degradation is a potential strategy for sensitizing HC to radiotherapy.
下咽癌（HC）治疗中放射疗法的使用正在增加，目前它是这种癌症的主要治疗选择。然而，一部分患者会出现放射抗性。在此，我们发现辐射会增加蛋白酶体基因表达，并且蛋白酶体组装依赖于HC中转录因子NRF1的诱导。通过筛选试验，我们确定了一种机制，即蛋白酶体介导的含DEP结构域的mTOR相互作用蛋白（DEPTOR）降解有助于辐射后mTORC1信号的升高。因此，用蛋白酶体抑制剂（PIs）治疗后，DEPTOR的稳定化抑制了辐射升高的mTORC1信号，并最终使HC对放射治疗敏感。从机制上讲，PIs不仅中断了DEPTOR的去泛素化和降解，还抑制了β-TrCP介导的DEPTOR泛素化。在临床上，HC细胞中高水平的DEPTOR与放射治疗敏感性和良好预后相关。通过靶向蛋白酶体介导的降解来稳定DEPTOR是使HC对放射治疗敏感的一种潜在策略。
