Abstract A24: The transcriptional regulator JAB1 is a novel regulator of osteosarcoma development

Osteosarcoma is the most common malignant primary bone tumor. Osteosarcoma patients with metastases have a survival rate of only 25%. Therefore, a greater understanding of the pathogenesis of osteosarcoma is needed for better diagnosis and treatment. An emerging player in tumorigenesis is the transcriptional cofactor JAB (also named CSN5, COPS5), through its effects on cell proliferation, differentiation, survival, and cell cycle progression. Our laboratory has recently shown that Jab1 plays critical roles in the successive steps of mouse skeletal development by affecting master developmental regulators Runx2 and Sox9 in a context-dependent manner. As an essential component of the highly conserved COP9 signalosome complex, JAB1 is over-expressed in many different types of cancers, including breast and lung, but has not been studied in bone cancer. Thus, the goal of this study is to determine the potential role of JAB1 in the pathogenesis of osteosarcoma. We first determined, by immunohistochemistry, that JAB1 was highly expressed in over 75% of fifty-one osteosarcoma patients’ biopsy samples. Next, to determine whether down-regulating JAB1 expression in osteosarcoma reduces tumorigenesis, we knocked down JAB1 expression in a highly metastatic osteosarcoma cell line 143B, using shRNA lentiviral vectors. The JAB1 knockdown cells exhibited significantly reduced cell proliferation, colony formation, and motility compared with the control cells. Therefore, these results suggest that down-regulating JAB1 expression in osteosarcoma might reduce tumorigenesis. We will determine whether the down-regulation of JAB1 in 143B cells reduces tumorigenesis in vivo in xenograft experiments. On the other hand, to study the consequence of JAB1 over-expression in vivo, we have generated Col1a1-JAB1 transgenic mouse lines using a well-characterized 2.3kb Col1a1 promoter to over-express JAB1 in osteoblasts specifically. Previous mouse genetic studies have shown that p53 is a critical factor in the development of osteosarcoma, and that JAB1 is a negative regulator of p53 activity in other cancers in cell lines. To test whether increased JAB1 over-expression promotes bone tumorigenesis in vivo in a p53-dependent manner, we crossed Cola1-JAB1 transgenic mice, which had no gross abnormality and no osteosarcoma occurrence, with p53+/- heterozygous mice. Impressively, our preliminary study so far indicates that significantly more Cola1-JAB1; p53+/- double transgenic mice developed solid tumors on limbs than p53+/- control mice at the 11-month time point. Thus, our study provided a novel mouse model to study the JAB1-p53 interaction in osteosarcoma development. Ultimately, new therapies based on controlling the JAB1-mediated tumorigenesis will open new avenues for treating osteosarcoma and other cancers. Citation Format: Lindsay Bashur, Robin Elliott, Guang Zhou. The transcriptional regulator JAB1 is a novel regulator of osteosarcoma development. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A24.