Tumor Suppressor RARRES1/TIG1 in Prostate Cancer Biomarker to Therapeutic Target

Prostate cancer (PC) is a major health concern for US men and is expected to result in approximately 218,000 new cases and about 32,000 deaths in 2010. African-American (AA) men have a 60% higher incidence rate and twice the death rate of white men, and it is the second leading cause of cancer-related death in AA men. Epidemiologic and basic science studies suggest that decreased vitamin D exposure, and to some extent also vitamin A, are associated with an increased risk of prostate cancer. AA also tend to have lower intakes of vitamin A and D, and population mean serum vitamin D levels of 16 ng/mL have been reported in AA as compared to 26 ng/mL in Caucasian population. Vitamin A and vitamin D possess anti-cancer properties with very different differentiating activities, but similar cell death inducing activities. We have identified TIG1/RARRES1 as a vitamin D and A induced gene in prostate cancer cell lines. TIG1 is a poorly understood putative tumor suppressor gene that is methylated and dramatically downregulated in human prostate cancer. In 2011, the Byers and Kumar group demonstrated that RARRES1 regulates cytoskeletal architecture by modulating tubulin tyrosination, which is important for tumor progression, and identified a novel area for intervention; this forms the basis for this highly innovative Synergistic Idea Award. In this proposal, our collaborative/synergistic preliminary data further demonstrate (a) the expression and regulation of RARRES1/TIG1 by vitamin A and D in PC cell lines, (b) downregulation of RARRES1 in prostate cancer, (c) that RARRES1 induces apoptotic response in multiple PC cell lines, and (d) that TIG1 is localized at cleavage furrow and may regulate cellular cytokinesis. We hypothesize that TIG1 is a molecular target of vitamin D and its modulation regulates prostate cancer progression. Further, TIG1 expression is modulated by multiple mechanisms such as methylation, transcriptional modulation, and miRNA-mediated regulation. In this proposal, we will characterize the role of TIG/RARRES1 in prostate cancer progression and its significance as molecular biomarker and therapeutic target. Specifically, we will study (1) whether expression of RARRES1/TIG1 protein correlates with prostate cancer progression in human tissues and a mouse model, (2) whether TIG1 modulates cell proliferation and tumorigenicity, and (3) what mechanisms are involved in the regulation of TIG1/RARRES1. TIG1/RARRES1 is a novel putative tumor suppressor that likely plays an important role in PC progression and as a molecular target of vitamin A and D action. This proposal as presented will characterize TIG1 gene in PC and will explore and catalogue the expression pattern of TIG1 in AA and Caucasian (CA) prostate cancer patients. AAs as a group have the highest incidence and death rate from prostate cancer in the world. As is the case with other therapies that target protein receptors such as Iressa and Herceptin, identification of appropriate patients for therapy is essential. Although not an explicit aim of the current proposal, these studies could lead to other studies that might identify a group of prostate cancer patients that are candidates for treatment with vitamin A, vitamin D or its noncalcemic analogues with or without concomitant anti-androgen therapy. Partnership synergy in the proposal is evident by bringing complementary scientific expertise and resources by the partnering Principal Investigators to joint laboratory meetings and data-sharing activities. For example, the University of the District of Columbia (UDC) does not have an animal facility. As Dr. Byers is Director of Shared Resources at Georgetown-Lombardi and the Director of the Translation Technologies and Resources component of the recently awarded National Institutes of Health Clinical Translational Science Award, the Georgetown University (GU)-UDC synergism makes brings a large amount of value added to this work. Also, both investigators have a long record of educating and mentoring talented underrepresented minorities, and the work proposed will provide rotation opportunities for students in the joint GU/UDC graduate program.