| First Author | Lee JH | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 22 | Pages | 6182-6199.e29 |
| PubMed ID | 39243762 | Mgi Jnum | J:358053 |
| Mgi Id | MGI:7779304 | Doi | 10.1016/j.cell.2024.08.014 |
| Citation | Lee JH, et al. (2024) TGF-beta and RAS jointly unmask primed enhancers to drive metastasis. Cell 187(22):6182-6199.e29 |
| abstractText | Epithelial-to-mesenchymal transitions (EMTs) and extracellular matrix (ECM) remodeling are distinct yet important processes during carcinoma invasion and metastasis. Transforming growth factor beta (TGF-beta) 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-beta 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-beta. These regulatory properties segregate the fibrogenic EMT program from RAS-independent TGF-beta gene responses and illuminate the operation and vulnerabilities of a bifunctional program that promotes metastatic outgrowth. |
