RCCD1-JMJD5 coordinate histone demethylation to promote platinum resistance in non-small cell lung cancer via FN1-mediated epithelial-mesenchymal transition.
5 affiliations
- 1Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
- 2Postgraduate·Training Base Alliance of Wenzhou Medical University·(Zhejiang Cancer Hospital), Hangzhou, 310022, Zhejiang, China.
- 3Department of Pathology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. [email protected].
- 4Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China. [email protected].
- 5Postgraduate·Training Base Alliance of Wenzhou Medical University·(Zhejiang Cancer Hospital), Hangzhou, 310022, Zhejiang, China. [email protected].
Abstract
Chemoresistance remains a major obstacle to effective treatment of non-small cell lung cancer (NSCLC), yet the epigenetic mechanisms underlying platinum resistance remain incompletely understood. Here, we show that Jumonji C domain-containing protein 5 (JMJD5) promotes platinum resistance in NSCLC cells and xenograft tumors while inducing a slow-proliferative, mesenchymal-like phenotype characterized by enhanced migration, invasion, spheroid formation, and epithelial-mesenchymal transition (EMT). Mechanistically, JMJD5 interacted with RCC1 domain-containing protein 1 (RCCD1), and cisplatin treatment promoted their nuclear accumulation concomitant with reduced H3K36me2 levels. RCCD1 depletion attenuated JMJD5-associated H3K36me2 demethylation and reversed EMT-associated phenotypes and cisplatin resistance, supporting RCCD1 as a functional cofactor of JMJD5-mediated chromatin remodeling. Fibronectin 1 (FN1) was further identified as a downstream effector of this pathway. Genetic or pharmacological inhibition of FN1 suppressed JMJD5-induced migration and invasion and restored cisplatin sensitivity. Notably, JMJD5-dependent FN1 protein accumulation required ongoing protein synthesis without a corresponding increase in FN1 mRNA, suggesting post-transcriptional regulation. Consistently, elevated FN1 expression was associated with unfavorable overall survival in patients with lung cancer. Collectively, these findings reveal a JMJD5-RCCD1-H3K36me2-FN1 regulatory axis linking chemotherapy-induced epigenetic remodeling to EMT-associated platinum resistance and suggest that disruption of this pathway may represent a potential strategy for overcoming chemoresistance in NSCLC.
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BibTeX
@article{tan2026rccd1jmjd5,
title = {{RCCD1-JMJD5 coordinate histone demethylation to promote platinum resistance in non-small cell lung cancer via FN1-mediated epithelial-mesenchymal transition.}},
author = {Lili Tan and Yinghui Tong and Wanying Zhou and Xinyue Ma and Qilu Fang and Yan Feng and Xueping Xiang and Luo Fang},
journal = {Molecular biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00625-y},
url = {https://europepmc.org/article/MED/42905309},
note = {CC BY},
}
RIS
TY - JOUR
TI - RCCD1-JMJD5 coordinate histone demethylation to promote platinum resistance in non-small cell lung cancer via FN1-mediated epithelial-mesenchymal transition.
AU - Lili Tan
AU - Yinghui Tong
AU - Wanying Zhou
AU - Xinyue Ma
AU - Qilu Fang
AU - Yan Feng
AU - Xueping Xiang
AU - Luo Fang
PY - 2026
DA - 2026/10/21
JO - Molecular biomedicine
DO - 10.1186/s43556-026-00625-y
UR - https://europepmc.org/article/MED/42905309
AB - Chemoresistance remains a major obstacle to effective treatment of non-small cell lung cancer (NSCLC), yet the epigenetic mechanisms underlying platinum resistance remain incompletely understood. Here, we show that Jumonji C domain-containing protein 5 (JMJD5) promotes platinum resistance in NSCLC cells and xenograft tumors while inducing a slow-proliferative, mesenchymal-like phenotype characterized by enhanced migration, invasion, spheroid formation, and epithelial-mesenchymal transition (EMT). Mechanistically, JMJD5 interacted with RCC1 domain-containing protein 1 (RCCD1), and cisplatin treatment promoted their nuclear accumulation concomitant with reduced H3K36me2 levels. RCCD1 depletion attenuated JMJD5-associated H3K36me2 demethylation and reversed EMT-associated phenotypes and cisplatin resistance, supporting RCCD1 as a functional cofactor of JMJD5-mediated chromatin remodeling. Fibronectin 1 (FN1) was further identified as a downstream effector of this pathway. Genetic or pharmacological inhibition of FN1 suppressed JMJD5-induced migration and invasion and restored cisplatin sensitivity. Notably, JMJD5-dependent FN1 protein accumulation required ongoing protein synthesis without a corresponding increase in FN1 mRNA, suggesting post-transcriptional regulation. Consistently, elevated FN1 expression was associated with unfavorable overall survival in patients with lung cancer. Collectively, these findings reveal a JMJD5-RCCD1-H3K36me2-FN1 regulatory axis linking chemotherapy-induced epigenetic remodeling to EMT-associated platinum resistance and suggest that disruption of this pathway may represent a potential strategy for overcoming chemoresistance in NSCLC.
SN - 2662-8651
ER -