Abstract
Abstract UHRF1 is an essential epigenetic reader and writer overexpressed in multiple human cancers, including retinoblastoma and osteosarcoma. For these tumors, metastasis remains the most significant fatal complication for treatment. Genetic alterations at the RB transcriptional corepressor 1 (RB1) gene are associated with initiation, increased mortality, metastasis, and poor response to chemotherapy. However, the precise mechanism(s) 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 retinoblastoma and osteosarcoma. UHRF1 is a multifunctional protein involved in epigenetic regulation and has been shown to have protein-protein interactions with RB. Further, the RB/E2F pathway directly regulates UHRF1 expression. Using genetic engineered mouse models, we found that UHRF1 is essential for retinoblastoma formation. We have also studied the role of UHRF1 in other RB-dependent malignancies, including osteosarcoma. Our results indicate that UHRF1 is overexpressed in most human osteosarcomas. Loss-of-function studies using UHRF1 shRNA knockdowns and CRISPR/Cas9 knockouts indicate that reduction of UHRF1 levels in human osteosarcoma cells results in decreased proliferation, migration and invasion. Strikingly, induction of UHRF1 overexpression in normal mesenchymal stem cells induces increased cell migration and invasion. We evaluated the role of UHRF1 in osteosarcoma development by knocking-out Uhrf1 in genetically engineered mouse models of osteosarcoma (p53 cKO: Osx-cre p53lox/lox and p53/Rb1 DKO: Osx-cre p53lox/lox Rb1lox/lox), to create p53/Uhrf1 DKO (Osx-cre p53lox/lox Uhrf1lox/lox) and p53/Rb1/Uhrf1 TKO (Osx-cre p53lox/lox Rb1lox/lox Uhrf1lox/lox) mice. Uhrf1 abrogation leads to a significant increase in survival in p53/Rb1/Uhrf1 TKO mice compared to their p53/Rb1 DKO littermate controls. While 100% of p53/Rb1 DKO mice develop tumors, 12.5% of p53/Rb1/Uhrf1 TKO mice did not, confirmed using microCT/PET imaging. Further, p53/Rb1/Uhrf1 TKO showed a significant reduction in the rate and number of lung metastasic nodules compared to p53/Rb1 DKO. Even though UHRF1 is overexpressed in osteosarcomas with wild type Rb1 (p53 cKO tumors), we found no significant difference in the median survival of p53/Uhrf1 DKO compared to p53 cKO littermate controls. These results suggest that UHRF1 overexpression is a significant contributor of the poor prognosis associated with loss of Rb1. Altogether, our data indicates that UHRF1 overexpression plays a significant role in osteosarcoma proliferation, migration, invasion, and metastasis, which translates in reduced survival mice with osteosarcoma. Our studies suggest that UHRF1 may play a role in carcinogenesis and is a putative biomarker and anticancer therapeutic target. Citation Format: Claudia A. Benavente, Stephanie C. Wu, Loredana Zocchi. UHRF1 overexpression is a significant driver of tumor progression in RB-mediated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2148.
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