2. Academic Validation
  3. PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target

PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target

  • Cell Death Dis. 2023 Oct 11;14(10):671. doi: 10.1038/s41419-023-06201-4.
Shaifali Singh # 1 2 3,  Nai Yang Yeat # 1 2 4,  Ya-Ting Wang 1,  Shu-Yu Lin 1,  I-Ying Kuo 5 6,  Kuen-Phon Wu 1 2,  Won-Jing Wang 7,  Wen-Ching Wang 3,  Wu-Chou Su 8,  Yi-Ching Wang 5 6,  Ruey-Hwa Chen 9 10
Affiliations

Affiliations

  • 1 Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan.
  • 2 Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan.
  • 3 Institute of Molecular & Cellular Biology and Department of Life Science, National Tsing Hua University, Hsinchu, 300, Taiwan.
  • 4 Department of Chemistry, National Tsing Hua University, Hsinchu, 300, Taiwan.
  • 5 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
  • 6 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
  • 7 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 8 Division of Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.
  • 9 Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan. rhchen@gate.sinica.edu.tw.
  • 10 Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan. rhchen@gate.sinica.edu.tw.
  • # Contributed equally.
PMID: 37821451 DOI: 10.1038/s41419-023-06201-4
Abstract

Aberrant overexpression or activation of EGFR drives the development of non-small cell lung Cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin Ligase and an association of WDR4 high expression with poor prognosis of lung Cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4-based ubiquitin Ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung Cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.

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