TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system

Lin, San‐Yih; Lee, Soo Ok; Lee, Yi Fen; Miyamoto, Hiroshi; Yang, Dong Rong; Li, Gonghui; Chang, Chawnshang

doi:10.1093/carcin/bgu052

Cited by 28 publications

(49 citation statements)

References 33 publications

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“…This is in contrast to an early study showing TR4 might suppress PCa initiation (6), suggesting that TR4 might play dual roles with a suppressor role in PCa initiation and a promoter role in PCa S/P cells invasion. Mechanism dissection suggested that TR4 might inhibit PCa initiation via positively regulating DNA damage-repair related gene ATM, thus enhancing DNA repair to prevent tumorigenesis.…”

Section: Discussioncontrasting

confidence: 99%

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TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression

Zhu

Yang

Sun

et al. 2015

Molecular Cancer Therapeutics

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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.

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Section: Discussioncontrasting

confidence: 99%

“…Results from TR4 knockout (TR4KO) mice studies have shown that TR4 may play key roles to influence embryonic development, stem cell pluripotency and progression of several diseases including metabolic disorders and various tumors (2–6). …”

Section: Introductionmentioning

confidence: 99%

TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression

Zhu

Yang

Sun

et al. 2015

Molecular Cancer Therapeutics

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“…Interestingly, a survey of PCa samples also found that one allele of the TR4 gene is deleted in 9% of PCa patients (SJ Lin, CY Lin, K Izumi, E Yan, X Niu, DR Yang, N Wang, Li G and C Chang, unpublished observations). These results indicate that TR4 is a tumor suppressor gene in the early development of PCa (Lin et al 2014). However, in vitro migration/invasion assays and in vivo mouse studies also found that TR4 promoted migration/invasion of various PCa cells via modulation of CCL2/CCR2 axis, indicating that TR4 can enhance PCa metastasis (XF Ding, DR Yang, SO Lee, YL Chen, LQ Xia, SJ Lin, SC Yu, YJ Niu, GH Li and C Chang, unpublished observations).…”

Section: Cancermentioning

confidence: 66%

“…C/C mice developed PIN and formed PCa tumors at 15 months (Lin et al 2014). Interestingly, a survey of PCa samples also found that one allele of the TR4 gene is deleted in 9% of PCa patients (SJ Lin, CY Lin, K Izumi, E Yan, X Niu, DR Yang, N Wang, Li G and C Chang, unpublished observations).…”

Section: Cancermentioning

confidence: 94%

Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases

Liu

Lin

et al. 2014

Endocrine-Related Cancer

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Peroxisome proliferator-activated receptor g (PPARg, NR1C3) and testicular receptor 4 nuclear receptor (TR4, NR2C2) are two members of the nuclear receptor (NR) superfamily that can be activated by several similar ligands/activators including polyunsaturated fatty acid metabolites, such as 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, as well as some anti-diabetic drugs such as thiazolidinediones (TZDs). However, the consequences of the transactivation of these ligands/activators via these two NRs are different, with at least three distinct phenotypes. First, activation of PPARg increases insulin sensitivity yet activation of TR4 decreases insulin sensitivity. Second, PPARg attenuates atherosclerosis but TR4 might increase the risk of atherosclerosis. Third, PPARg suppresses prostate cancer (PCa) development and TR4 suppresses prostate carcinogenesis yet promotes PCa metastasis. Importantly, the deregulation of either PPARg or TR4 in PCa alone might then alter the other receptor's influences on PCa progression. Knocking out PPARg altered the ability of TR4 to promote prostate carcinogenesis and knocking down TR4 also resulted in TZD treatment promoting PCa development, indicating that both PPARg and TR4 might coordinate with each other to regulate PCa initiation, and the loss of either one of them might switch the other one from a tumor suppressor to a tumor promoter. These results indicate that further and detailed studies of both receptors at the same time in the same cells/organs may help us to better dissect their distinct physiological roles and develop better drug(s) with fewer side effects to battle PPARg-and TR4-related diseases including tumor and cardiovascular diseases as well as metabolic disorders.

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“…A total of 8 mice were housed in a specific pathogen-free laboratory, airconditioned, with a 12/12 h light/dark cycle. Subcutaneous implantation was performed as previously described (27) where mice were injected subcutaneously with DUSP1-Vector or DUSP1-OE SGC996 cells. A total of 1x10 6 SGC996 stable cells (mixed with Matrigel in a ratio of 1:1) were injected subcutaneously.…”

Section: Rt-qpcrmentioning

confidence: 99%

DUSP1 enhances the chemoresistance of gallbladder cancer via the modulation of the p38 pathway and DNA damage/repair system

Fang

et al. 2018

Oncol Lett

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Abstract. Cisplatin (CDDP) is a commonly used drug for gallbladder cancer (GBC) chemotherapy. However, resistance to CDDP treatment results in relapse. Therefore, there is a need for the development of more effective treatment strategies to overcome chemoresistance. Dual-specificity phosphatase 1 (DUSP1) was reported to be involved in the resistance of a number of chemotherapeutic agents and was revealed to be highly expressed in CDDP-resistant GBC cells and CDDP-treated tumor types compared with normal cells or tissues in the present study. DUSP1 was revealed to inhibit the cytotoxicity of CDDP in two GBC cell lines, SGC996 and GBC-SD. P38 mitogen-activated protein kinases may be involved in the mechanism of chemoresistance. Furthermore, the number of DNA double-strand breaks in SGC996 OE cells was reduced compared with SGC996 vector cells indicating DUSP1 may attenuate the chemotherapeutic efficiency. Due to its potency against CDDP treatment, DUSP1 may be a promising target to overcome chemoresistance in GBC therapy. IntroductionGallbladder cancer (GBC) has a high occurrence among populations in the Andean area, Native Americans and Mexican Americans (1). GBC is often diagnosed at a late stage due to its unapparent symptoms at the early stage (2). Surgery is currently the primary option for GBC treatment alongside a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP), which is a common choice for advanced GBC (3,4). Although chemotherapy exerts a therapeutic effect in a number of patients, chemoresistance eventually occurs in patients that receive chemotherapy (5).CDDP is one of the most widely used cytotoxic anticancer drugs (6-9). CDDP mainly reacts with the N7-position of guanine, forming inter-and intra-strand DNA cross-links and blocks replication and transcription, and may result in replication-mediated double-strand breaks (DSBs) (10,11). However, resistance to these drugs undermines their curative potential. The resistance to CDDP and numerous other chemotherapeutic agents is partially due to a wide range of genetic and epigenetic alterations which result in abnormal cell survival (12)(13)(14). In the present study, the expression of a number of chemotherapy resistance-associated genes (DUSP1, HIF-1α, MDR1, MRP1) was compared between CDDP-resistant SGC996 and GBC-SD cells and normal SGC996 and GBC-SD cells. Notably, one gene (dual-specificity phosphatase 1 (DUSP1)) expression was markedly increased in the established CDDP-resistant cells compared with the normal cells. Using an in vivo assay, DUSP1 expression in subcutaneous tumors was also elevated following CDDP treatment.DUSP1 is one member of the DUSP family, which consists of a total of 25 members. The expression of DUSP1 is cancer-dependent (15). In a range of epithelial tumor types including pancreatic ductal adenocarcinoma (PDAC), non-small-cell lung cancer, breast, ovarian, gastric and early-stage prostate cancer, DUSP1 was revealed to be overexpressed, however it was decreased in hepatocellular carcinoma (16)(17)(18)(19). The DUSP fami...

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TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system

Cited by 28 publications

References 33 publications

TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression

TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression

Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases

DUSP1 enhances the chemoresistance of gallbladder cancer via the modulation of the p38 pathway and DNA damage/repair system

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