The FBXW7–KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism
F-box and WD repeat domain-containing 7 (FBXW7) is a tumor suppressor that targets various oncoproteins for degradation, but its role in modulating cancer-associated fibroblasts (CAFs) in the tumor microenvironment remains elusive. Here, we report that FBXW7 expression is gradually downregulated in CAFs during the progression of human pancreatic and lung cancers. Mechanically, FBXW7 inhibits histone lysine methyltransferase 2 (KMT2) methyltransferase activity via retinoblastoma binding protein 5 (RbBP5) binding, whereas FBXW7 depletion abrogates the binding to activate KMT2, leading to increased H3K4 methylations and global upregulation of gene expression. Activation of the interleukin-17 (IL-17) signaling pathway triggers the secretion of cytokines and chemokines to promote migration, invasion, and sphere formation of lung cancer cells. Coinjection of Fbxw7-depleted mouse embryonic fibroblasts with cancer cells enhances in vivo tumor growth, demonstrating a paracrine effect. Hypoxia downregulates CAF FBXW7 via ETS proto-oncogene 1 (ETS1) to increase H3K4 methylation, whereas conditioned media from hypoxia-exposed CAFs promotes migration and invasion of pancreatic cancer cells, highlighting FBXW7's tumor-suppressing role through KMT2 inactivation.
Authors
- Zhang Jia-gui
- Xiufang Xiong (ORCID: https://orcid.org/0000-0001-6842-3673)
- Huiyin Lan (ORCID: https://orcid.org/0000-0002-7925-0066)
- Jing Huang (ORCID: https://orcid.org/0000-0002-0481-8702)
- Fengbiao Mao (ORCID: https://orcid.org/0000-0003-0852-4266)
- Zhipeng Zhu (ORCID: https://orcid.org/0000-0001-5685-410X)
- Yi Sun (ORCID: https://orcid.org/0000-0002-5841-4287)
- Bo Zhou (ORCID: https://orcid.org/0000-0002-7816-7017)
- Yali Dou (ORCID: https://orcid.org/0000-0002-4040-1429)
- Yaohui He (ORCID: https://orcid.org/0000-0002-8235-8924)
- Wen Liu (ORCID: https://orcid.org/0000-0003-3434-4162)
- Yan Lü (ORCID: https://orcid.org/0000-0002-5004-4656)
- Xiaoming Peng (ORCID: https://orcid.org/0009-0006-1728-4515)
- Lu Yin (ORCID: https://orcid.org/0009-0008-3327-9788)
- Alex Ayoub (ORCID: https://orcid.org/0009-0004-7034-1721)
- Siyuan Wang (ORCID: https://orcid.org/0000-0001-6550-4064)
- Mingjia Tan
Institutions
- University of Southern California (US)
- Tata Institute of Fundamental Research (IN)
- Target (United States) (US)
- Shanghai Jiao Tong University (CN)
- Xiamen University (CN)
- Peking University (CN)
- University of Michigan (US)
- Shanghai Ninth People's Hospital (CN)
- Women's Hospital, School of Medicine, Zhejiang University (CN)
- Peking University Third Hospital (CN)
- Ministry of Education (ET)
- Zhejiang University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-03-24
- DOI
- https://doi.org/10.1073/pnas.2423130122
- Citations
- 6
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- National Natural Science Foundation of China
- Beijing Nova Program
- National Key Research and Development Program of China
- Natural Science Foundation of Zhejiang Province