title: Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.
abstract: The cytokine TGF-beta acts as a tumor suppressor in normal epithelial cells and during the early stages of tumorigenesis. During malignant progression, cancer cells can switch their response to TGF-beta and use this cytokine as a potent oncogenic factor; however, the mechanistic basis for this is poorly understood. Here we demonstrate that downregulation of disabled homolog 2 (DAB2) gene expression via promoter methylation frequently occurs in human squamous cell carcinomas (SCCs) and acts as an independent predictor of metastasis and poor prognosis. Retrospective microarray analysis in an independent data set indicated that low levels of DAB2 and high levels of TGFB2 expression correlate with poor prognosis. Immunohistochemistry, reexpression, genetic knockout, and RNAi silencing studies demonstrated that downregulation of DAB2 expression modulated the TGF-beta/Smad pathway. Simultaneously, DAB2 downregulation abrogated TGF-beta tumor suppressor function, while enabling TGF-beta tumor-promoting activities. Downregulation of DAB2 blocked TGF-beta-mediated inhibition of cell proliferation and migration and enabled TGF-beta to promote cell motility, anchorage-independent growth, and tumor growth in vivo. Our data indicate that DAB2 acts as a tumor suppressor by dictating tumor cell TGF-beta responses, identify a biomarker for SCC progression, and suggest a means to stratify patients with advanced SCC who may benefit clinically from anti-TGF-beta therapies.
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, United Kingdom.
authors.forename: Adèle
authors.initials: A
authors.lastname: Hannigan
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
authors.forename: Clare
authors.initials: C
authors.lastname: Orange
authors.forename: Darren I
authors.initials: DI
authors.lastname: O'Brien
authors.forename: Reshma
authors.initials: R
authors.lastname: Shah
authors.forename: Nelofer
authors.initials: N
authors.lastname: Syed
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Spender
authors.forename: Blanca
authors.initials: B
authors.lastname: Herrera
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Thurlow
authors.forename: Laura
authors.initials: L
authors.lastname: Lattanzio
authors.forename: Martino
authors.initials: M
authors.lastname: Monteverde
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Maurer
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
authors.forename: David C K
authors.initials: DC
authors.lastname: Chu
authors.forename: Catharine M L
authors.initials: CM
authors.lastname: West
authors.forename: Max
authors.initials: M
authors.lastname: Patridge
authors.forename: Karin A
authors.initials: KA
authors.lastname: Oien
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Nicholson
authors.forename: Milena
authors.initials: M
authors.lastname: Gasco
authors.forename: Tim
authors.initials: T
authors.lastname: Crook
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Inman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D045744:Cell Line, Tumor; D002465:Cell Movement; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D006258:Head and Neck Neoplasms / Q000209:etiology; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins