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.

放射疗法在下咽癌 (HC) 治疗中的应用正在增加，目前它是这种癌症的主要治疗选择。然而，放射抗性发生在一定比例的患者中。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，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 信号传导的升高。因此，在用蛋白酶体抑制剂 (PI) 治疗后，DEPTOR 的稳定化抑制了辐射升高的 mTORC1 信号传导，并最终使 HC 对放疗敏感。机械地，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的泛素化。临床上，HC 细胞中高水平的 DEPTOR 与对放射治疗的敏感性和良好的预后相关。通过靶向蛋白酶体介导的降解来稳定 DEPTOR 是一种使 HC 对放射治疗敏感的潜在策略。