Stabilization of DEPTOR sensitizes hypopharyngeal cancer to radiotherapy via targeting degradation.
Stabilization of DEPTOR sensitizes hypopharyngeal cancer to radiotherapy via targeting degradation.
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DEPTOR 的稳定通过靶向降解使下咽癌对放射治疗敏感。
DOI：
10.1016/j.omto.2022.08.002
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发表时间：
2022-09-15
期刊：
影响因子：
--
通讯作者：
Chen, Yong
中科院分区：
文献类型：
--
作者：
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
放射治疗在下咽癌(HC)治疗中的应用日益增多，目前已成为下咽癌的主要治疗手段。然而，在一定比例的患者中会出现辐射抵抗。在这里，我们发现辐射增加了蛋白酶体基因的表达，并且蛋白酶体的组装依赖于转录因子NRF1在HC中的诱导。通过筛选实验，我们确定了蛋白酶体介导的含有DEP结构域的mTOR相互作用蛋白(DEPTOR)的降解有助于辐射后mTORC1信号的上调。因此，在蛋白酶体抑制剂(PIs)治疗后，DEPTOR的稳定化抑制了辐射上调的mTORC1信号，最终使HC对放射治疗增敏。从机制上讲，Pis不仅阻断了去泛素化和DEPTOR的降解，而且还抑制了β-TrCP介导的DEPTOR泛素化。临床上，HC细胞中高水平的DEPTOR与放射治疗的敏感性和良好的预后有关。通过靶向蛋白酶体介导的降解来稳定DEPTOR是使HC对放射治疗增敏的一种潜在策略。Wang等人。研究发现，下咽癌(HC)细胞中高水平的DEPTOR与放疗的敏感性和良好的预后有关。通过靶向蛋白酶体介导的降解来稳定DEPTOR是使HC对放射治疗增敏的一种潜在策略。
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. Wang et al. found that high DEPTOR levels in hypopharyngeal cancer (HC) cells were associated with the sensitivity to radiotherapy and favorable prognosis. Stabilizing DEPTOR through targeting proteasome-mediated degradation is a potential strategy for sensitizing HC to radiotherapy.
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