title: SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis.
abstract: The epithelial-to-mesenchymal transition (EMT) is important for the development of cancer metastases and organ fibrosis, conditions prevalent in aging. Because sirtuins affect the pathology of aging, we tested the effect of SirT1 on EMT. Reduced SIRT1 levels in HMLER breast cancer cells led to increased metastases in nude mice, and the loss of SIRT1 in kidney tubular epithelial cells exacerbated injury-induced kidney fibrosis. SIRT1 reduces EMT in cancer and fibrosis by deacetylating Smad4 and repressing the effect of TGF-β signaling on MMP7, a Smad4 target gene. Consequently, less E-cadherin is cleaved from the cell surface and β-catenin remains bound to E-cadherin at the cell-cell junctions. Our findings suggest that the SIRT1/Smad4/β-catenin axis may be a target for diseases driven by EMT.
authors.affiliation: Glenn Laboratory for the Science of Aging and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Simic
authors.forename: Eric O
authors.initials: EO
authors.lastname: Williams
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Gong
authors.forename: Michael
authors.initials: M
authors.lastname: Bonkowski
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000473:pathology; D020783:Matrix Metalloproteinase 7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D034741:RNA, Small Interfering; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D020783:Matrix Metalloproteinase 7; D056564:Sirtuin 1