2. Academic Validation
  3. JMJD5 inhibits lung cancer progression by facilitating EGFR proteasomal degradation

JMJD5 inhibits lung cancer progression by facilitating EGFR proteasomal degradation

  • Cell Death Dis. 2023 Oct 9;14(10):657. doi: 10.1038/s41419-023-06194-0.
Jing Shen # 1,  Guiling Liu # 2,  Hongyan Qi 3,  Xueping Xiang 4,  Jimin Shao 5
Affiliations

Affiliations

  • 1 Department of Pathology and Pathophysiology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. shenjingwzy@zju.edu.cn.
  • 2 Department of Pathology and Pathophysiology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 3 Experimental Teaching Center of Basic Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 4 Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 5 Department of Pathology and Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • # Contributed equally.
PMID: 37813845 DOI: 10.1038/s41419-023-06194-0
Abstract

Aberrant activation of epidermal growth factor receptor (EGFR) signaling is closely related to the development of non-small cell lung Cancer (NSCLC). However, targeted EGFR therapeutics such as tyrosine kinase inhibitors (TKIs) face the challenge of EGFR mutation-mediated resistance. Here, we showed that the reduced JmjC domain-containing 5 (JMJD5) expression is negatively associated with EGFR stability and NSCLC progression. Mechanically, JMJD5 cooperated with E3 Ligase HUWE1 to destabilize EGFR and EGFR TKI-resistant mutants for proteasomal degradation, thereby inhibiting NSCLC growth and promoting TKI sensitivity. Furthermore, we identified that JMJD5 can be transported into recipient cells via extracellular vesicles, thereby inhibiting the growth of NSCLC. Together, our findings demonstrate the tumor-suppressive role of JMJD5 in NSCLC and suggest a putative therapeutic strategy for EGFR-related NSCLC by targeting JMJD5 to destabilize EGFR.

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