The T-box transcription factors TBX2 and TBX3 are overexpressed in several cancers and are able to bypass senescence by repressing ARF and p21 WAF1/CIP1/SDII . Although these studies suggest that they may both contribute to the oncogenic process by repressing common targets, whether they have redundant or distinct roles in cancers where they are both overexpressed remains to be elucidated. Importantly, when Tbx2 function is inhibited in melanoma cells lacking Tbx3, the cells senesce, but whether this is possible in melanoma cells overexpressing both proteins is not known. An understanding of this issue may have important implications for the design of an effective pro-senescence therapy. In this study, the authors used a sh-RNA approach to knock down TBX2 and TBX3 individually in 2 human melanoma cell lines that overexpress both these factors and then examined their specific involvement in the oncogenic process. They demonstrate, using in vitro and in vivo cell proliferation, as well as colony-and tumor-forming ability and cell motility assays, that TBX2 and TBX3 have distinct roles in melanoma progression. In the tested lines, although TBX2 could promote proliferation and transformation and was required by primary melanoma cells for immortality, TBX3 was required for tumor formation and cell migration. These findings were reproducible in a human breast cancer cell line, which confirms that TBX2 and TBX3, although highly homologous, do not have redundant roles in the transformation process of cancers where they are both overexpressed. These results have important implications for the development of new cancer treatments and in particular for melanoma, which is a highly aggressive and intractable cancer.

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The emergence of drug resistant tumours that are able to escape cell death pose a major problem in the treatment of cancers. Tumours develop resistance to DNA-damaging chemotherapeutic agents by acquiring the ability to repair their DNA. Combination therapies that induce DNA damage and disrupt the DNA damage repair process may therefore prove to be more effective against such tumours. The developmentally important transcription factor TBX2 has been suggested as a novel anticancer drug target, as it is overexpressed in several cancers and possesses strong anti-senescence and pro-proliferative functions. Importantly, we recently showed that when TBX2 is silenced, we are able to reverse several features of transformation in both breast cancer and melanoma cells. Overexpression of TBX2 has also been linked to drug resistance and we have shown that its ectopic expression results in genetically unstable polyploidy cells with resistance to cisplatin. Whether the overexpression of endogenous TBX2 levels is associated with cisplatin resistance in TBX2-driven cancers has, however, not been shown. To address this we have silenced TBX2 in a cisplatin-resistant breast cancer cell line and we show that knocking down TBX2 sensitises the cells to cisplatin by disrupting the ATM-CHK2-p53 signalling pathway. Cell cycle analyses demonstrate that when TBX2 is knocked down there is an abrogation of an S-phase arrest but a robust G2/M arrest that correlates with a reduction in phosphorylated CHK2 and p53 levels. This prevents DNA repair resulting in TBX2-deficient cells entering mitosis with damaged DNA and consequently undergoing mitotic catastrophe. These results suggest that targeting TBX2 in combination with chemotherapeutic drugs such as cisplatin could improve the efficacy of current anticancer treatments.