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

Abstract

The cytokine TGF-β 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-β 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-β/Smad pathway. Simultaneously, DAB2 downregulation abrogated TGF-β tumor suppressor function, while enabling TGF-β tumor-promoting activities. Downregulation of DAB2 blocked TGF-β-mediated inhibition of cell proliferation and migration and enabled TGF-β 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-β responses, identify a biomarker for SCC progression, and suggest a means to stratify patients with advanced SCC who may benefit clinically from anti-TGF-β therapies.

Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2

“…Dab2 may be a tumor suppressor, but in late cancer stages it is also functionally important for tumorigenesis by promotion of EMTmediated metastasis (Prunier and Howe, 2005;Chaudhury et al, 2010). During the progression of human squamous cell carcinoma, downregulation of Dab2 switches transforming growth factor-b from tumorsuppressor to tumor-promoting functions (Hannigan et al, 2010). Clearly, Dab2 appears to have a dual role in tumor progression.…”

Targeting TGF-β Signaling for Therapeutic Gain

“…In carcinomas, many tumors lose the growth inhibitory response to TGF-b, but still respond to this ligand but in a protumorigenic manner, such as increased migration, invasion, and epithelial-mesenchymal transition (EMT). Thus, depending on the tumor type and the stage of tumor progression, TGF-b may potently suppress or promote cancer progression through direct actions on the tumor cells (Gomis et al 2006b;Hannigan et al 2010), presumably through its control over differential gene expression programs (see below).…”

“…Taking into account the many activities of TGF-b and its pleiotropic actions, major efforts focus on identifying alternative targets that influence the TGF-b signaling pathway, with a strong incentive to identify drugs that might block TGF-b's tumor progressing activities while sparing tumor-suppressing activities. Many studies identified pivotal intratumoral players that regulate such a balance-for example, disabled homolog 2 (DAB2), which is epigenetically down-regulated in human SCCs, resulting in attenuation of TGF-b tumor suppressor activity to enable TGF-b tumor-promoting activities, including promotion of cell motility, anchorage-independent growth, and in vivo tumor growth (Hannigan et al 2010). Another example includes the pivotal role played by differential expression of three isoforms of C/EBPb that are generated by usage of distinct translational start sites during tumor progression.…”

The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression

“…115,116 Furthermore, Dab2 participates in the endocytosis of TβRII and promotes signaling of TGFβ through canonical Smad signaling. Dab2 can decrease E-cadherin levels and upregulate the mesenchymal marker vimentin 117 demonstrating not only a role for Dab2 in EMT, but also in the regulation of E-cadherin.…”