2. Academic Validation
  3. Stabilization of DEPTOR sensitizes hypopharyngeal cancer to radiotherapy via targeting degradation

Stabilization of DEPTOR sensitizes hypopharyngeal cancer to radiotherapy via targeting degradation

  • Mol Ther Oncolytics. 2022 Aug 5:26:330-346. doi: 10.1016/j.omto.2022.08.002.
Xuecen Wang 1 2,  Zhirui Cao 3 2,  Xin Yue 1 4 2,  Tingyu Liu 5,  Gesi Wen 6,  Dongmei Jiang 7,  Weijian Wu 8,  Liyuan Le 9,  Yan Wang 1,  Chengtao Wang 1,  Ziyang Wang 2,  Meng Jin 1,  Meiyan Zhu 1,  Shasha He 1,  Xiaoyue Zhang 1,  Xianzhang Bu 8,  Ran-Yi Liu 5,  Zhenwei Peng 1,  Yong Chen 1
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 2 Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 3 The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 4 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 6 Department of Clinical Research, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
  • 7 Department of Pathology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
  • 8 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 9 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510089, China.
PMID: 36090478 DOI: 10.1016/j.omto.2022.08.002
Abstract

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.

Keywords

DEPTOR; hypopharyngeal cancer; mTORC1; proteasome; radioresistance.

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