Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts

Jean Albrengues, Thomas Bertero, Eloise Grasset, Stephanie Bonan, Majdi Maiel, Isabelle Bourget, Claude Philippe, Cecilia Herraiz Serrano, Samia Benamar, Olivier Croce, Victoria Sanz-Moreno, Guerrino Meneguzzi, Chloe C. Feral, Gael Cristofari, Cedric Gaggioli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

271 Citations (Scopus)
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Abstract

Carcinoma-associated fibroblasts (CAF) mediate the onset of a proinvasive tumour microenvironment. The proinflammatory cytokine LIF reprograms fibroblasts into a proinvasive phenotype, which promotes extracellular matrix remodelling and collective invasion of cancer cells. Here we unveil that exposure to LIF initiates an epigenetic switch leading to the constitutive activation of JAK1/STAT3 signalling, which results in sustained proinvasive activity of CAF. Mechanistically, p300-histone acetyltransferase acetylates STAT3, which, in turn, upregulates and activates the DNMT3b DNA methyltransferase. DNMT3b methylates CpG sites of the SHP-1 phosphatase promoter, which abrogates SHP-1 expression, and results in constitutive phosphorylation of JAK1. Sustained JAK1/STAT3 signalling is maintained by DNA methyltransferase DNMT1. Consistently, in human lung and head and neck carcinomas, STAT3 acetylation and phosphorylation are inversely correlated with SHP-1 expression. Combined inhibition of DNMT activities and JAK signalling, in vitro and in vivo, results in long-term reversion of CAF-associated proinvasive activity and restoration of the wild-type fibroblast phenotype.

Original languageEnglish
Article number10204
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 15 Dec 2015

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