Unexpected mechanism controlling growth vs. senescence in cancer

November 24, 2021 — Ludwig researchers Sizhu Lu, Pakavarin Louphrasitthiphol, Colin Goding and their colleagues have now shown how a transcriptional regulator called TBX2 plays a crucial role in senescence, a state of stable cell cycle arrest that can halt cancer initiation. Their findings appeared in the journal Genes and Development.

TBX2 is a DNA-binding transcription factor (or a regulator of gene expression) previously linked to transcriptional repression in development and senescence bypass and proliferation in cancer. But how it exerts its effects has so far been unclear. The team found that TBX2 acts downstream of PI3K signaling, which is important for senescence bypass in melanomas driven by a mutated BRAF gene.

Their 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—repressing genes that block the cell cycle but maintaining expression of genes associated with promoting cell cycle progression. TBX2 is thus a crucial regulator of cancer initiation and progression.

Since depletion of TBX2 can reactivate senescence in human melanoma, targeting TBX2 activity may represent an avenue toward pro-senescence anti-cancer therapy.


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