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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:p>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\u2019s tumor-suppressing role through KMT2 inactivation.<\/jats:p>","DOI":"10.1073\/pnas.2423130122","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T15:13:45Z","timestamp":1742829225000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["The FBXW7\u2013KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism"],"prefix":"10.1073","volume":"122","author":[{"given":"Lu","family":"Yin","sequence":"first","affiliation":[{"name":"Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang 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Yin Data from \u201cThe FBXW7-KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism.\u201d NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE164134. Deposited 1 January 2021."},{"key":"e_1_3_4_52_2","unstructured":"L. Yin Data from \u201cThe FBXW7-KMT2 axis in cancer-associated fibroblasts controls tumor growth via an epigenetic-paracrine mechanism.\u201d NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE164135. 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