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 three different mouse models, we found TR4 could prevent or delay prostate cancer (PCa)/prostatic intraepithelial neoplasia 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 PCa 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 small interfering RNA-induced tumorigenesis in cell transformation assays. Immunohistochemical staining in human PCa tissue microarrays revealed 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. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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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.
    Molecular Endocrinology 04/2014; 28(6):me20131422. DOI:10.1210/me.2013-1422 · 4.02 Impact Factor
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    ABSTRACT: The testicular nuclear receptor 4 (TR4) is a member of the nuclear receptor superfamily that mediates various biological functions with key impacts on metabolic disorders and tumor progression. Here we demonstrate that TR4 may play a positive role in prostate cancer (PCa) CD133+ stem/progenitor (S/P) cell invasion. Targeting TR4 with lentiviral silencing RNA significantly suppressed PCa CD133+ S/P cell invasion both in vitro and in vivo. Mechanism dissection found that TR4 transcriptionally regulates the oncogene EZH2 via binding to its 5' promoter region. The consequences of targeting TR4 to suppress EZH2 expression may then suppress the expression of its downstream key metastasis-related genes including NOTCH1, TGFβ1, SLUG and MMP9. Rescue approaches via adding the EZH2 reversed the TR4-mediated PCa S/P cell invasion. Together, these results suggest that the TR4→EZH2 signaling may play a critical role in the PCa S/P cell invasion and may allow us to develop a better therapy to battle the PCa metastasis. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 04/2015; 14(6). DOI:10.1158/1535-7163.MCT-14-0971 · 5.68 Impact Factor
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    ABSTRACT: A recent report indicated that the TR4 nuclear receptor might suppress the prostate cancer (PCa) initiation via modulating the DNA damage/repair system. Knocking-out peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that shares similar ligands/activators with TR4, promoted PCa initiation. Here we found 9% of PCa patients have one allele of PPARG deletion. Results from in vitro cell lines and in vivo mouse model indicated that during PCa initiation TR4 roles might switch from suppressor to enhancer in prostate cells when PPARG was deleted or suppressed (by antagonist GW9662). Mechanism dissection found targeting TR4 in the absence of PPARG might alter the stem cell population and epithelial-mesenchymal transition (EMT) signals. Together, these results suggest that whether TR4 can enhance or suppress PCa initiation may depend on the availability of PPARG and future potential therapy via targeting PPARG to battle PPARG-related diseases may need to consider the potential side effects of TR4 switched roles during the PCa initiation.
    04/2015; 2(2):142-50. DOI:10.18632/oncoscience.121
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