Article

TR4 Nuclear Receptor Functions as a Tumor Suppressor for Prostate Tumorigenesis via Modulation of DNA Damage/Repair System.

Carcinogenesis (Impact Factor: 5.27). 02/2014; DOI: 10.1093/carcin/bgu052
Source: PubMed

ABSTRACT Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, plays important roles in metabolism, fertility, and aging. The linkage of TR4 functions in cancer progression, however, remains unclear. Using 3 different mouse models, we found TR4 could prevent or delay prostate cancer/PIN development. Knocking down TR4 in human RWPE1 and mouse mPrE normal prostate cells promoted tumorigenesis under carcinogen challenge, suggesting TR4 may play a suppressor role in prostate cancer initiation. Mechanism dissection in both in vitro cell lines and in vivo mice studies found that knocking down TR4 led to increased DNA damage with altered DNA repair system that involved the modulation of ATM expression at the transcriptional level, and addition of ATM partially interrupted the TR4 siRNA-induced tumorigenesis in cell transformation assays. Human PCa tissue microarray IHC staining found ATM expression is highly correlated with TR4 expression. Together, these results suggest TR4 may function as a tumor suppressor to prevent or delay prostate tumorigenesis via regulating ATM expression at the transcriptional level.

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