TGF-β and RAS jointly unmask primed enhancers to drive metastasis

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.

上皮 - 间质转化（EMTs）和细胞外基质（ECM）重塑是癌症侵袭和转移过程中不同但重要的过程。转化生长因子β（TGF - β）和RAS通过SMAD和RAS反应元件结合蛋白1（RREB1）发出信号，共同触发EMT和纤维化因子的表达，作为癌细胞中一种常见转录反应的两个不同分支。在此，我们证明这两个分支共同形成了一个肺腺癌转移的程序，并确定了将组成基因的表达与TGF - β和RAS输入联系起来的染色质决定因素。RREB1定位于组蛋白H2A.Z负载的核小体中纤维化基因白细胞介素 - 11（IL11）、血小板衍生生长因子 - B（PDGFB）和透明质酸合酶2（HAS2）以及EMT转录因子SNAI1增强子上的H4K16acK20ac标记，使这些增强子在响应TGF - β时能被SMAD4 - INO80核小体重塑复合物激活。这些调控特性将纤维化EMT程序与不依赖RAS的TGF - β基因反应区分开来，并阐明了一个促进转移性生长的双功能程序的运作及其弱点。