Major finding: USP1 deubiquitinates and stabilizes ID1, ID2, and ID3.
Impact: A mechanism for ID protein stabilization in cancer and development is identified.
Clinical relevance: Differentiation therapies may be effective in osteosarcoma.
Inhibitor of DNA-binding (ID) proteins are key developmental regulators that block cellular differentiation in multiple tissues. Because the members of the ID family (ID1–4) are highly expressed in pluripotent cells and aberrantly stabilized in tumors, they are believed to play critical roles in cancer stem cell biology. Williams and colleagues performed a screen of human deubiquitinases (DUB) to identify candidates whose overexpression could increase ID2 levels, and found that ubiquitin-specific peptidase 1 (USP1) specifically stabilized, bound, and deubiquitinated ID2 in vitro. Analysis of USP1 gene expression patterns revealed that this DUB is more highly expressed in osteosarcoma samples compared to normal bone and correlates with high ID2 protein levels. It remains unclear how USP1 is upregulated, but amplification of the USP1 locus has been identified in a subset of osteosarcomas. In osteosarcoma cell lines, USP1 knockdown led to decreased levels of ID1, ID2, and ID3 (ID4 is not proteasomally regulated), indicating that USP1 is required for ID protein stabilization. ID proteins antagonize basic-helix-loop-helix (bHLH) transcription factors that normally induce differentiation and block proliferation. USP1 knockdown increased bHLH transcriptional activity and induced p21-mediated cell cycle arrest in osteosarcoma cells. Combined suppression of IDs 1 to 3 phenocopied the effect of USP1 knockdown on osteosarcoma proliferation, suggesting that USP1-dependent stabilization of ID proteins may be a novel mechanism of cell cycle checkpoint bypass in oncogenic transformation. Indeed, forced overexpression of USP1 in NIH3T3 cells induced anchorage-independent growth that could be blocked by ID knockdown, and both USP1 and ID2 overexpression promoted aggressive tumor growth in mice. The authors also demonstrate that USP1 is required for bone development and that its overexpression inhibits osteogenic differentiation of mesenchymal stem cells. Collectively, these data suggest that stabilization of ID proteins by USP1 in osteosarcoma promotes tumor proliferation and maintenance of a stemlike phenotype that may be targetable by therapies that induce differentiation.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.
