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

Carcinogenesis (Impact Factor: 5.33). 02/2014; 35(6). DOI: 10.1093/carcin/bgu052
Source: PubMed


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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    ABSTRACT: Testicular nuclear receptor 4 (TR4), also known as NR2C2, belongs to the nuclear receptor superfamily that shares high homology with the testicular nuclear receptor 2 (TR2). The natural ligands of TR4 remained unclear until the recent discoveries of several energy/lipid sensors including the polyunsaturated fatty acids metabolites, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, and their synthetic ligands, thiazolidinediones, used for treatment of diabetes. TR4 is widely expressed throughout the body, particularly concentrated in the testis, prostate, cerebellum, and hippocampus. It has been shown to play important roles in cerebellar development, forebrain myelination, folliculogenesis, gluconeogenesis, lipogenesis, muscle development, bone development, and prostate cancer progression. Here we provide a comprehensive summary of TR4 signaling including its upstream ligands/activators/suppressors, transcriptional co-activators/repressors, downstream targets, and their in vivo functions with potential impacts on TR4-related diseases. Importantly, sharing similar ligands/activators with another key nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ), raised several interesting questions about how these 2 nuclear receptors may collaborate with or counteract each other's function in the related diseases. Clear dissection of such molecular mechanisms and their differential roles in various diseases may help researchers to design new potential drugs with better efficacy and fewer side effects to battle TR4 and PPARγ involved diseases.
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    ABSTRACT: Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, may play important roles to modulate the metabolic diseases and prostate tumorigenesis. Here we found TR4 could increase prostate cancer (PCa) cell invasion. Mechanism dissection revealed that TR4 might increase PCa cell invasion via decreasing the miR-373-3p expression that resulted in the activation of the TGFβR2/p-Smad3 signals. The in vivo mouse model using orthotopically xenografted CWR22Rv1 cell line transfected with luciferase-reporter confirmed in vitro cell line studies showing TR4 increased PCa metastasis via decreasing the miR-373-3p expression. Together, these data suggest that TR4 may increase PCa metastasis via a newly identified signal and targeting these TR4/miR-473-3p/TGFβR2/p-Smad3 signals using TR4 antagonist or TR4-siRNA or miR-373-3p may allow us to develop a new potential therapeutic approach to better suppress PCa metastasis.
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