Senescence halts the cell cycle and puts the brakes on cancer initiation. For example, when an oncogene is activated, tumour formation is blocked if senescence pathways are switched on but cancer may develop if senescence is bypassed. Although several key proteins involved in triggering or bypassing senescence have been found, there are many gaps in our knowledge of switching between senescence or proliferation gene expression programmes. Ludwig researchers Sizhu Lu, Pakavarin Louphrasitthiphol, Colin Goding, and their colleagues, have now uncovered how a transcriptional regulator called TBX2 plays a crucial role in this process; their findings have been published in the journal Genes and Development.
TBX2 is a DNA-binding transcription factor previously linked to transcriptional repression in development, and senescence bypass and proliferation in cancer. However, how it exerts its biological effects has been poorly defined. Signalling via the PI3K kinase pathway is important for senescence bypass in melanoma, for example for those carrying mutations in the BRAF oncogene, and the team found that TBX2 acts downstream of PI3K signalling.
Although a DNA sequence motif bound by TBX2 had previously been identified (a T-box motif), few target genes had been confirmed. By tagging the endogenous TBX2 protein in melanoma cells, Colin Goding’s team were able to find many new TBX2 binding sites, including unexpected binding to different DNA motifs known to bind other transcription factors. Indeed, the researchers found that TBX2 interacts with a wide range of transcription factors and is likely to modulate their activity in cells. This surprising finding showed that TBX2 can either repress or activate transcriptional programmes, depending on the molecular context.
In BRAF-mutated melanoma, TBX2 binds and is required for expression of E2F1, a key anti-senescence cell cycle regulator. Specifically, TBX2 recruits components of the BCOR/polycomb repressive complex 1.1 (PRC1.1) complex to the gene encoding E2F1.
More broadly, this research vastly expands knowledge of the repertoire of genes bound and regulated by TBX2. It provides a fundamentally different perspective on TBX2 function in senescence and development: rather than acting as a dedicated transcriptional repressor, it can also activate genes, thereby both repressing genes that block the cell cycle but maintaining expression of genes associated with promoting cell cycle progression. TBX2 is thus a crucial regulator in cancer initiation and progression. Importantly, as depletion of TBX2 can reactivate senescence in human melanoma, targeting TBX2 activity may represent an avenue toward pro-senescence anti-cancer therapy.