TGF-β and RAS jointly unmask primed enhancers to drive metastasis Journal Article
| Authors: | Lee, J. H.; Sánchez-Rivera, F. J.; He, L.; Basnet, H.; Chen, F. X.; Spina, E.; Li, L.; Torner, C.; Chan, J. E.; Yarlagadda, D. V. K.; Park, J. S.; Sussman, C.; Rudin, C. M.; Lowe, S. W.; Tammela, T.; Macias, M. J.; Koche, R. P.; Massagué, J. |
| Article Title: | TGF-β and RAS jointly unmask primed enhancers to drive metastasis |
| Abstract: | Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor β (TGF-β) and RAS, signaling through SMAD and RAS-responsive element-binding protein 1 (RREB1), jointly trigger expression of EMT and fibrogenic factors as two discrete arms of a common transcriptional response in carcinoma cells. Here, we demonstrate that both arms come together to form a program for lung adenocarcinoma metastasis and identify chromatin determinants tying the expression of the constituent genes to TGF-β and RAS inputs. RREB1 localizes to H4K16acK20ac marks in histone H2A.Z-loaded nucleosomes at enhancers in the fibrogenic genes interleukin-11 (IL11), platelet-derived growth factor-B (PDGFB), and hyaluronan synthase 2 (HAS2), as well as the EMT transcription factor SNAI1, priming these enhancers for activation by a SMAD4-INO80 nucleosome remodeling complex in response to TGF-β. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-β gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth. © 2024 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; protein expression; dna binding protein; human cell; genetics; dna-binding proteins; nonhuman; polymerase chain reaction; adenocarcinoma; mass spectrometry; protein analysis; animal cell; mouse; animal; metabolism; animals; mice; metastasis; gene expression; transforming growth factor beta; lung neoplasms; animal experiment; transcription factor; pathology; cell line, tumor; transcription factors; fibrosis; lung tumor; gene expression regulation; gene expression regulation, neoplastic; lung adenocarcinoma; histone; chromatin; chromatin immunoprecipitation; tumor cell line; neoplasm metastasis; ras protein; real time polymerase chain reaction; gentamicin; ras proteins; snail family transcription factors; penicillin derivative; transcription factor snail; histones; ras; emt; enhancer region; enhancer elements, genetic; nucleosome; nucleosomes; enhancer; epithelial-mesenchymal transition; platelet derived growth factor b; streptomycin; epithelial mesenchymal transition; adenocarcinoma of lung; smad4 protein; luciferin; smad; tgf-β; interleukin-11; interleukin 11; humans; human; female; article; single cell rna seq; hyaluronan synthases; hyaluronate synthetase; snai1 protein, human |
| Journal Title: | Cell |
| Volume: | 187 |
| Issue: | 22 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2024-10-31 |
| Start Page: | 6182 |
| End Page: | 6199.e29 |
| Language: | English |
| DOI: | 10.1016/j.cell.2024.08.014 |
| PUBMED: | 39243762 |
| PROVIDER: | scopus |
| PMCID: | PMC12035776 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Joan Massague -- Source: Scopus |
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