Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.

Adèle Hannigan; Paul Smith; Gabriela Kalna; Cristiana Lo Nigro; Clare Orange; Darren I O'Brien; Reshma Shah; Nelofer Syed; Lindsay C Spender; Blanca Herrera; Johanna K Thurlow; Laura Lattanzio; Martino Monteverde; Meghan E Maurer; Francesca M Buffa; Jelena Mann; David C K Chu; Catharine M L West; Max Patridge; Karin A Oien; Jonathan A Cooper; Margaret C Frame; Adrian L Harris; Louise Hiller; Linda J Nicholson; Milena Gasco; Tim Crook; Gareth J Inman

doi:10.1172/JCI36125

Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.

Adèle Hannigan, Paul Smith, Gabriela Kalna, Cristiana Lo Nigro, Clare Orange, Darren I O'Brien, Reshma Shah, Nelofer Syed, Lindsay C Spender, Blanca Herrera, Johanna K Thurlow, Laura Lattanzio, Martino Monteverde, Meghan E Maurer, Francesca M Buffa, Jelena Mann, David C K Chu, Catharine M L West, Max Patridge, Karin A OienJonathan A Cooper, Margaret C Frame, Adrian L Harris, Louise Hiller, Linda J Nicholson, Milena Gasco, Tim Crook, Gareth J Inman

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	The Journal of clinical investigation
Volume	120
Issue number	8
DOIs	https://doi.org/10.1172/JCI36125
Publication status	Published - Aug 2010

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Hannigan, A., Smith, P., Kalna, G., Lo Nigro, C., Orange, C., O'Brien, D. I., Shah, R., Syed, N., Spender, L. C., Herrera, B., Thurlow, J. K., Lattanzio, L., Monteverde, M., Maurer, M. E., Buffa, F. M., Mann, J., Chu, D. C. K., West, C. M. L., Patridge, M., ... Inman, G. J. (2010). Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter. The Journal of clinical investigation, 120(8). https://doi.org/10.1172/JCI36125

@article{e8eab8c2c67641a295c115ecffcec9f9,

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.",

author = "Ad{\`e}le Hannigan and Paul Smith and Gabriela Kalna and {Lo Nigro}, Cristiana and Clare Orange and O'Brien, {Darren I} and Reshma Shah and Nelofer Syed and Spender, {Lindsay C} and Blanca Herrera and Thurlow, {Johanna K} and Laura Lattanzio and Martino Monteverde and Maurer, {Meghan E} and Buffa, {Francesca M} and Jelena Mann and Chu, {David C K} and West, {Catharine M L} and Max Patridge and Oien, {Karin A} and Cooper, {Jonathan A} and Frame, {Margaret C} and Harris, {Adrian L} and Louise Hiller and Nicholson, {Linda J} and Milena Gasco and Tim Crook and Inman, {Gareth J}",

note = "GM066257, NIGMS NIH HHS, United StatesR01 GM066257, NIGMS NIH HHS, United States, Cancer Research UK, United Kingdom",

year = "2010",

month = aug,

doi = "10.1172/JCI36125",

language = "English",

volume = "120",

journal = "The Journal of clinical investigation",

issn = "1558-8238",

publisher = "American Society for Clinical Investigation",

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}

Hannigan, A, Smith, P, Kalna, G, Lo Nigro, C, Orange, C, O'Brien, DI, Shah, R, Syed, N, Spender, LC, Herrera, B, Thurlow, JK, Lattanzio, L, Monteverde, M, Maurer, ME, Buffa, FM, Mann, J, Chu, DCK, West, CML, Patridge, M, Oien, KA, Cooper, JA, Frame, MC, Harris, AL, Hiller, L, Nicholson, LJ, Gasco, M, Crook, T & Inman, GJ 2010, 'Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.', The Journal of clinical investigation, vol. 120, no. 8. https://doi.org/10.1172/JCI36125

TY - JOUR

T1 - Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.

AU - Hannigan, Adèle

AU - Smith, Paul

AU - Kalna, Gabriela

AU - Lo Nigro, Cristiana

AU - Orange, Clare

AU - O'Brien, Darren I

AU - Shah, Reshma

AU - Syed, Nelofer

AU - Spender, Lindsay C

AU - Herrera, Blanca

AU - Thurlow, Johanna K

AU - Lattanzio, Laura

AU - Monteverde, Martino

AU - Maurer, Meghan E

AU - Buffa, Francesca M

AU - Mann, Jelena

AU - Chu, David C K

AU - West, Catharine M L

AU - Patridge, Max

AU - Oien, Karin A

AU - Cooper, Jonathan A

AU - Frame, Margaret C

AU - Harris, Adrian L

AU - Hiller, Louise

AU - Nicholson, Linda J

AU - Gasco, Milena

AU - Crook, Tim

AU - Inman, Gareth J

N1 - GM066257, NIGMS NIH HHS, United StatesR01 GM066257, NIGMS NIH HHS, United States, Cancer Research UK, United Kingdom

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

U2 - 10.1172/JCI36125

DO - 10.1172/JCI36125

M3 - Article

C2 - 20592473

SN - 1558-8238

VL - 120

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

IS - 8

ER -

Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter.

Abstract

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