2. Academic Validation
  3. E3 ubiquitin ligase ITCH-mediated proteasomal degradation of WBP2 sensitizes breast cancer cells to chemotherapy through restraining AMOTL2/c-JUN axis

E3 ubiquitin ligase ITCH-mediated proteasomal degradation of WBP2 sensitizes breast cancer cells to chemotherapy through restraining AMOTL2/c-JUN axis

  • Biochem Pharmacol. 2024 Dec 19:232:116720. doi: 10.1016/j.bcp.2024.116720.
Maoshu Zhu 1,  Weimin Zhong 2,  Solomon Wong 3,  Xianyang Luo 4,  Zhicong Hong 4,  Juli Lin 5,  Junhua Wu 6,  Yi Zhou 7,  Zhongquan Qi 8,  Shuai Chen 9
Affiliations

Affiliations

  • 1 School of Medicine, Guangxi University, Nanning, 530004, China; The Fifth Hospital of Xiamen, Xiamen 361101, Fujian, China.
  • 2 The Fifth Hospital of Xiamen, Xiamen 361101, Fujian, China.
  • 3 School of Medicine, Guangxi University, Nanning, 530004, China.
  • 4 Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361005, China; Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen 361005, Fujian, China.
  • 5 Department of Breast Surgery, Women and Children's Hospital, School of Medicine, Xiamen University, No.10, Zhenhai Road, Xiamen 361003, Fujian Province, China.
  • 6 Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361005, China; Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen 361005, Fujian, China. Electronic address: wuelle@sina.com.
  • 7 Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361005, China; Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen 361005, Fujian, China. Electronic address: zhouyixm@sina.com.
  • 8 School of Medicine, Guangxi University, Nanning, 530004, China. Electronic address: yxyyz@gxu.edu.cn.
  • 9 Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361005, China; Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen 361005, Fujian, China. Electronic address: chenshuai@xmu.edu.cn.
PMID: 39709035 DOI: 10.1016/j.bcp.2024.116720
Abstract

Our study had demonstrated that WW domain-binding protein 2 (WBP2) conferred chemoresistance in breast Cancer (BC). However, the underlying mechanism remains unclear. Herein, a decreased expression of itchy E3 ubiquitin protein Ligase (ITCH) was observed in drug-resistant BC tissues which negatively regulated the expression of WBP2. However, ligase-deficient ITCH C830A mutant missed this function. WBP2 upregulation-initiated the chemoresistance to doxorubicin was reversed by exogenous ITCH, which was not affected by ITCH C830A mutant. In in vivo model, exogenous ITCH obstructed WBP2-mediated chemoresistance, which was destroyed by the Proteasome Inhibitor (MG132). Upon RNA Sequencing, the excessive activations of angiomotin-like 2 (AMOTL2) and c-Jun (Jun proto-oncogene, AP-1 transcription factor subunit) were screened in WBP2-overexpressed BC cells. Additionally, AMOTL2 and endonuclear phosphorylated c-Jun were at a high level in chemoresistant BC tumors and WBP2-overexpressed BC cells. Mechanistically, exogenous ITCH transfection prevented the activation of AMOTL2/c-Jun induced by WBP2 overexpression, which was restored by MG132-mediated inhibition on ITCH activation. The increase of multiple drug-resistant proteins caused by WBP2 upregulation were restrained by AMOTL2 knockdown or c-Jun antagonist, respectively. Our findings present how ITCH/WBP2 signaling functions to link the intricate AMOTL2/c-Jun signaling networks in chemoresistant BC cells. Targeting WBP2 combined with c-Jun inhibitors may be a potential option to overcome chemoresistance in breast Cancer patients.

Keywords

Angiomotin-like 2; Chemoresistant breast cancer; Itchy E3 ubiquitin protein ligase; WW domain-binding protein 2; c-JUN.

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