The Anti-proliferative Function of the TGF-β1 Signaling Pathway Involves the Repression of the Oncogenic TBX2 by Its Homologue TBX3

A growing body of work has shown that the highly homologous T-box transcription factors TBX2 and TBX3 play critical but distinct roles in embryonic development and cancer progression. For example, TBX2 and TBX3 are up-regulated in several cancers and recent evidence suggests that whereas TBX2 functions as a pro-proliferative factor, TBX3 inhibits cell proliferation but promotes cancer cell migration and invasion. While the molecular mechanisms regulating these functions of TBX2 and TBX3 are poorly understood we recently reported that the TGF-β1 signaling pathway up-regulates TBX3 expression to mediate, in part, its well described anti-proliferative and pro-migratory roles. The TBX3 targets responsible for these functions were however not identified. Here we reveal for the first time that the TGF-β1 signaling pathway represses TBX2 transcriptionally and we provide a detailed mechanism to show that this is mediated by TBX3. Furthermore, we implicate the down-regulation of TBX2 in the anti-proliferative function of the TGF-β1-TBX3 axis. These findings have important implications for our understanding of the regulation of TBX2 and TBX3 and shed light on the mechanisms involved in the anti-proliferative and pro-migratory roles of TGF-β1. Background: The transcription factor TBX3 regulates the anti-proliferative function of the TGF-β1 pathway but its downstream target(s) responsible for this is unknown. Results: TBX3 downstream of TGF-β1 signaling represses TBX2 to inhibit proliferation. Conclusion: The down-regulation of TBX2 is required for the anti-proliferative function of the TGF-β1-TBX3 axis. Significance: This study sheds light on the mechanisms involved in the anti-proliferative role of TGF-β1.