| Literature DB >> 26898331 |
Charles J David1, Yun-Han Huang1, Mo Chen2, Jie Su1, Yilong Zou1, Nabeel Bardeesy3, Christine A Iacobuzio-Donahue4, Joan Massagué5.
Abstract
TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β-sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-β. TGF-β-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.Entities:
Mesh：
Substances：
Year: 2016 PMID： 26898331 PMCID： PMC4801341 DOI： 10.1016/j.cell.2016.01.009
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582