The FBXW7-KMT 2 axis in cancer- associated fibroblasts controls tumor growth via an epigenetic- paracrine mechanism

• 成果类型: Article
• 署名作者: Yin, Lu; Zhang, Jiagui; Zhu, Zhipeng; Peng, Xiaojuan; Lan, Huiyin; Ayoub, Alex; Tan, Mingjia; Zhou, Bo; He, Yaohui; Wang, Siyuan; Lu, Yan; Liu, Wen; Xiong, Xiufang; Huang, Jing; Dou, Yali; Mao, Fengbiao; Sun, Yi
• 署名单位: Zhejiang University; Zhejiang University; Shanghai Jiao Tong University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Xiamen University; Zhejiang University; Zhejiang University; Zhejiang University; University of Southern California; University of Southern California; Zhejiang University; Zhejiang University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11496
• DOI: 10.1073/pnas.2423130122
• 发表日期: 2025-04-01
• 关键词: fbw7 ubiquitin ligase; methyltransferase activity; mll family; suppressor; PERSPECTIVES; methylation

摘要

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.