Abstract A41: Role of UHRF1 in tumorigenesis and metastasis of osteosarcoma

Abstract

Abstract Osteosarcoma is the eighth most common form of childhood cancer, with very limited advances in treatment over the past three decades. Osteosarcoma is a highly metastatic cancer, with 15-20% of osteosarcoma patients diagnosed after the cancer has already metastasized, causing the survival rate to be little over 50%. Common sites of metastasis include lung and liver. Loss of the retinoblastoma protein (RB) is associated with poor prognosis in osteosarcoma, as defined by shorter life span and heavier tumor burden. Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F pathway that is overexpressed in various cancers. We have confirmed using human mesenchymal stem cells (MSCs) and osteosarcoma cell lines that UHRF1 is directly regulated by the RB/E2F pathway in the bone lineage, and found that the UHRF1 gene is upregulated and its protein overexpressed in osteosarcoma. Using gain/loss-of-function assays to study the role of UHRF1 in osteosarcoma, we observed that UHRF1 is involved in promoting cell migration. To study the role of UHRF1 in osteosarcoma tumor development, we generated Uhrf1 conditional knockout mice. In this system, we use an Osterix-driven Cre recombinase (Osx-cre) to facilitate preosteoblast-specific loss of various combinations of genes. Osx-cre Tp53; Rb1 double knockout mice give rise to osteosarcoma and have a median survival of 26.7 weeks. Additional loss of Uhrf1 in Osx-cre Tp53; Rb1 double knockout mice (Osx-cre Tp53; Rb1; Uhrf1 triple knockout mice) significantly delays the age of tumor onset to >47 weeks. Furthermore, triple knockout mice have a decreased frequency and number of lung and liver metastasis. In conclusion, we have strong evidences both in vitro and in vivo that UHRF1 is a crucial component in aiding osteosarcoma progression, and have identified its novel role in tumor metastasis. The high metastatic rate and low 5-year survival rate following metastasis of osteosarcoma make UHRF1 a promising target for therapeutics. Further studies on the mechanism by which UHRF1 overexpression contributes to osteosarcomagenesis, including tumor growth and dissemination, will strongly aid the process of drug development for anticancer treatment. Citation Format: Stephanie C. Wu, Claudia A. Benavente. Role of UHRF1 in tumorigenesis and metastasis of osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A41.