Department of Pathology and Pathophysiology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Experimental Teaching Center of Basic Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Cell Death Dis. 2023 Oct 9;14(10):657. doi: 10.1038/s41419-023-06194-0.
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.
表皮生长因子受体 (EGFR) 信号的异常激活与非小细胞肺癌 (NSCLC) 的发生发展密切相关。然而，针对 EGFR 的靶向治疗药物，如酪氨酸激酶抑制剂 (TKI)，面临着 EGFR 突变介导的耐药性挑战。在这里，我们表明，含 JmjC 结构域的 5 号蛋白 (JMJD5) 的表达减少与 EGFR 的稳定性和 NSCLC 的进展呈负相关。在机制上，JMJD5 与 E3 连接酶 HUWE1 合作，使 EGFR 及其 EGFR TKI 耐药突变体不稳定，通过蛋白酶体降解，从而抑制 NSCLC 的生长并促进 TKI 的敏感性。此外，我们发现 JMJD5 可以通过细胞外囊泡转移到受体细胞中，从而抑制 NSCLC 的生长。总之，我们的研究结果表明 JMJD5 在 NSCLC 中具有肿瘤抑制作用，并通过靶向 JMJD5 使 EGFR 不稳定来抑制 EGFR 相关 NSCLC，为其提供了一种潜在的治疗策略。
