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Tbx3 Represses E-Cadherin Expression and Enhances Melanoma Invasiveness

¹ Signalling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey, United Kingdom; ² Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford, United Kingdom; and ³ IFOM-IEO Campus, Milan, Italy

Requests for reprints: Colin R. Goding, Signalling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, RH8 0TL, United Kingdom. Phone: 44-0-1883-722-306; Fax: 44-0-1883-714-375; E-mail: C.Goding{at}mcri.ac.uk.

Key Words: Tbx3 • Tbx2 • E-cadherin • melanoma

The T-box transcription factors Tbx2 and Tbx3 are overexpressed in many cancers and in melanoma promote proliferation by actively suppressing senescence. Whether they also contribute to tumor progression via other mechanisms is not known. Here, we identify a novel role for these factors, providing evidence that Tbx3, and potentially Tbx2, directly repress the expression of E-cadherin, a keratinocyte-melanoma adhesion molecule whose loss is required for the acquisition of an invasive phenotype. Overexpression of Tbx2 and Tbx3 in melanoma cells down-regulates endogenous E-cadherin expression, whereas depletion of Tbx3, but not Tbx2, increases E-cadherin mRNA and protein levels and decreases melanoma invasiveness in vitro. Consistent with these observations, in melanoma tissue, Tbx3 and E-cadherin expression are inversely correlated. Depletion of Tbx3 also leads to substantial up-regulation of Tbx2. The results suggest that Tbx2 and Tbx3 may play a dual role during the radial to vertical growth phase transition by both inhibiting senescence via repression of p21^CIP1 expression, and enhancing melanoma invasiveness by decreasing E-cadherin levels. [Cancer Res 2008;68(19):7872–81]