Metastasis remains the most significant fatal complication in the treatment of osteosarcoma. Among the patients who develop metastasis, less than 1 in 5 survive. Genetic alterations at the RB transcriptional corepressor 1 (RB1) gene have been associated with increased mortality, metastasis and poor response to chemotherapy in osteosarcoma. However, the precise mechanism through which this occurs remains to be elucidated. Studies in our laboratory identified UHRF1 (Ubiquitin-like, containing PHD and RING Finger domains 1), as a gene that is upregulated and its protein overexpressed in osteosarcoma. UHRF1 is a multifunctional protein involved in epigenetic regulation that has been shown to interact with RB. Further, the RB/E2F pathway directly regulates UHRF1 expression. Our data indicates that targeting UHRF1 overexpression dramatically increases survival in mice bearing osteosarcoma tumors and reduces the rate and number of metastases. The goal of this proposal is to determine the mechanism(s) through which UHRF1 contributes to tumor progression to help design novel therapeutic interventions for the treatment of osteosarcoma. These studies also evaluate whether UHRF1 is a valid target for most osteosarcomas or only those bearing RB1 mutations. For this, we will define the role of UHRF1 in osteosarcoma pathogenesis and progression, focusing on its relationship with RB1 and define the roles of each of the UHRF1 functional domains in the UHRF1-associated migration and invasion in osteosarcoma. This proposal tests the hypothesis that gene expression alterations driven by UHRF1 underlie tumor progression and poor survival in osteosarcoma. Successful completion of this work is likely to directly influence the development of UHRF1 inhibitors relevant for therapeutic intervention for osteosarcoma and other cancers with UHRF1 overexpression.

Public Health Relevance

Metastasis remains the most significant complication of osteosarcoma. Among the patients who develop metastasis, less than 1 in 5 survive. Thus, there is a pressing clinical need to determine the factors responsible for metastasis in osteosarcoma in order to facilitate the development of new therapeutic strategies. Our limited understanding of the biology, which drives the spread of osteosarcoma from primary bone sites into lung tissue, has limited our ability to accomplish this. We identified UHRF1 as a protein overexpressed in osteosarcoma that plays a significant role in osteosarcoma metastasis. This project aims to further our understanding of the role of UHRF1 in tumor formation, progression and metastasis and further investigate its potential as therapeutic target for anti-cancer treatment. Given that UHRF1 is overexpressed in multiple cancers, this research proposal has the potential to impact human health beyond osteosarcoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Hildesheim, Jeffrey
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University of California Irvine
Schools of Pharmacy
United States
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