USP1 Deubiquitinates ID Proteins to Preserve a Mesenchymal Stem Cell Program in Osteosarcoma
Menée in vitro et à l'aide d'un modèle murin, cette étude montre que l'enzyme USP1, impliquée dans le processus de déubiquitination, joue un rôle essentiel pour les cellules souches caractéristiques des ostéosarcomes
Inhibitors of DNA binding (IDs) antagonize basic-helix-loop-helix (bHLH) transcription factors to inhibit differentiation and maintain stem cell fate. ID ubiquitination and proteasomal degradation occur in differentiated tissues, but IDs in many neoplasms appear to escape degradation. We show that the deubiquitinating enzyme USP1 promotes ID protein stability and stem cell-like characteristics in osteosarcoma. USP1 bound, deubiquitinated, and thereby stabilized ID1, ID2, and ID3. A subset of primary human osteosarcomas coordinately overexpressed USP1 and ID proteins. USP1 knockdown in osteosarcoma cells precipitated ID protein destabilization, cell-cycle arrest, and osteogenic differentiation. Conversely, ectopic USP1 expression in mesenchymal stem cells stabilized ID proteins, inhibited osteoblastic differentiation, and enhanced proliferation. Consistent with USP1 functioning in normal mesenchymal stem cells, USP1-deficient mice were osteopenic. Our observations implicate USP1 in preservation of the stem cell state that characterizes osteosarcoma and identify USP1 as a target for differentiation therapy. º USP1 deubiquitinates and stabilizes ID1, ID2, and ID3 º USP1 and ID proteins are coordinately overexpressed in osteosarcomas º USP1 or ID deficiency promotes osteogenic differentiation of osteosarcoma cells º USP1 represents a target for tumor differentiation therapy Identification of an enzyme that stabilizes inhibitors of differentiation opens up new avenues for tumor differentiation therapy.