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  • 1
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    Ion channel TRPM8 promotes hypoxic growth of prostate cancer cells via an O 2 ‐independent and RACK1 ‐mediated mechanism of HIF ‐1α stabilization
    Wiley ; 2014
    In:  The Journal of Pathology Vol. 234, No. 4 ( 2014-12), p. 514-525
    Details
    In: The Journal of Pathology, Wiley, Vol. 234, No. 4 ( 2014-12), p. 514-525
    Abstract: The growth adaptation of cancer cells to a hypoxic tumour microenvironment is mostly regulated by hypoxia‐induced transcription factor HIF ‐1. HIF ‐1 transcriptional activity is strictly controlled by protein levels of the HIF ‐1α subunit, which is tightly regulated by a well‐characterized O 2 ‐dependent ubiquitin ligase–proteasomal degradation pathway. The cold‐sensitive Ca 2+ channel protein TRPM8 exhibits increased expression in advanced prostate cancer. However, its exact functional roles in prostate cancer growth regulation are unclear and controversial. In this work, we show that TRPM8 promotes in vitro hypoxic growth capacities, drug resistance, and in vivo tumourigenicity, accompanied with enhanced HIF ‐1α protein levels. These effects are further potentiated by TRPM8 agonists but suppressed by TRPM8 gene knockdown and blocking with antagonists or TRPM8 antibody. TRPM8 ‐induced suppression of HIF ‐1α ubiquitination and enhanced HIF ‐1 transactivation were attenuated by forced RACK1 expression and TRPM8 overexpression reduced phospho‐ RACK1 levels, thus affecting its dimerization status, and promoted RACK1 binding to HIF ‐1α and calcineurin. These data indicate that TRPM8 ‐induced increase of HIF ‐1α protein in hypoxia‐ or normoxia‐exposed prostate cancer cells was mediated through a newly characterized Ca 2+ ‐dependent but O 2 ‐independent mechanism involving binding of RACK1 to HIF ‐1α and RACK1 ‐mediated ubiquitination of HIF ‐1α. Collectively, our study not only provides a mechanistic insight into how TRPM8 promotes the hypoxic growth adaptation of cancer cells via its promotion of RACK1 ‐mediated stabilization of HIF ‐1α but also suggests a potential therapeutic strategy for prostate cancer by targeting TRPM8 .Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2014.234.issue-4
    DOI: 10.1002/path.4413
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2014
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    detail.hit.zdb_id: 1475280-3
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  • 2
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    Abstract A21: Orphan nuclear receptor TLX recruits lysine-specific demethylase 1 to repress androgen receptor gene transcription and functions to promote hormone-resistant growth of prostate cancer cells
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 13_Supplement ( 2013-07-01), p. A21-A21
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 13_Supplement ( 2013-07-01), p. A21-A21
    Abstract: Prostate cancer (PCa) is the most frequently diagnosed type of cancer and the second leading cause of death from cancer in males in the United States. The initial growth of most localized PCa is slow and androgen-dependent. Thus, surgical treatment (prostatectomy) and hormone therapy (androgen deprivation) are effective initially. However, many patients relapse and progress to a fatal androgen-independent and bone-metastatic stage shortly when both primary and secondary hormone therapies fail. Unfortunately, the current options for the metastatic hormone-refractory PCa are still limited and mostly ineffective, resulting in high mortality of this disease. Although dysregulated androgen receptor (AR) signaling pathway has been proposed to contribute to the development of hormone-resistance, the involved mechanisms are still not fully defined. Our present findings revealed that the orphan nuclear receptor TLX (NR2E1) exhibited increased expression patterns in androgen-independent and antiandrogen-resistant PCa cells, and also the high-grade and hormone-refractory clinical PCa tissues. Stable overexpression of TLX in AR-positive LNCaP cells could promote both androgen-independent and antiandrogen-resistant cell growth in vitro, and enhance tumor growth capacity in castrated male SCID mice in vivo. Decreased expression of AR and AR target genes in LNCaP-TLX cells were identified, while results of AR-promoter driven luciferase reporter assay also revealed that TLX overexpression could suppress the AR transcription in non-prostatic HEK293 cells. Furthermore, we also identified the direct binding site of TLX on the AR promoter by chromatin immunoprecipitation analyses in TLX-transfected HEK293 cells. The molecular mechanism may involve the TLX-mediated recruitment of lysine-specific demethylase 1 (LSD1) as treatment with an inhibitor of LSD1 pargyline could reverse the transrepressive regulation of TLX on AR-promoter driven luciferase activity and restore AR gene expression levels in LNCaP cells. In summary, our results showed for the first time that overexpression of TLX might contribute to the hormone-resistant PCa cell growth and advanced progression of PCa. LSD1 might serve as a corepressor in TLX-mediated direct transrepression on AR gene expression. This work is partly supported by an RGC-General Research Fund CUHK461012. Citation Format: Lin Jia, Dinglan Wu, Shan Yu, Franky Leung Chan. Orphan nuclear receptor TLX recruits lysine-specific demethylase 1 to repress androgen receptor gene transcription and functions to promote hormone-resistant growth of prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A21.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.CEC13-A21
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 3
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    Nuclear receptor ERRα and transcription factor ERG form a reciprocal loop in the regulation of TMPRSS2:ERG fusion gene in prostate cancer
    Springer Science and Business Media LLC ; 2018
    In:  Oncogene Vol. 37, No. 48 ( 2018-11), p. 6259-6274
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 37, No. 48 ( 2018-11), p. 6259-6274
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-018-0409-7
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2008404-3
    detail.hit.zdb_id: 639046-8
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  • 4
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    Orphan nuclear receptor TLX functions as a potent suppressor of oncogene‐induced senescence in prostate cancer via its transcriptional co‐regulation of the CDKN1A ( p21 WAF1 / CIP1 ) and SIRT1 genes
    Wiley ; 2015
    In:  The Journal of Pathology Vol. 236, No. 1 ( 2015-05), p. 103-115
    Details
    In: The Journal of Pathology, Wiley, Vol. 236, No. 1 ( 2015-05), p. 103-115
    Abstract: Oncogene‐induced senescence is an important tumour‐suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor TLX ( NR2E1 ) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene‐induced senescence. We determined that TLX exhibited an increased expression in high‐grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest in vitro and in vivo , whereas its over‐expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin‐induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene‐induced senescence induced either by activated oncogene H‐ Ras G12V or knockdown of tumour suppressor PTEN , via a mechanism of direct but differential transcriptional regulation of two senescence‐associated genes, repression of CDKN1A and transactivation of SIRT1 . Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene‐induced senescence, and also suggests that targeting the senescence‐regulatory TLX is of potential therapeutic significance in prostate cancer. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2015.236.issue-1
    DOI: 10.1002/path.4505
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 3119-7
    detail.hit.zdb_id: 1475280-3
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  • 5
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    Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
    Springer Science and Business Media LLC ; 2020
    In:  Oncogene Vol. 39, No. 7 ( 2020-02-13), p. 1572-1589
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 39, No. 7 ( 2020-02-13), p. 1572-1589
    Abstract: Hepatocyte nuclear factor 4α (HNF4α, NR2A1) is a highly conserved member of the nuclear receptor superfamily. Recent advances reveal that it is a key transcriptional regulator of genes, broadly involved in xenobiotic and drug metabolism and also cancers of gastrointestinal tract. However, the exact functional roles of HNF4α in prostate cancer progression are still not fully understood. In this study, we determined the functional significance of HNF4α in prostate cancer. Our results showed that HNF4α exhibited a reduced expression pattern in clinical prostate cancer tissues, prostate cancer cell lines and xenograft model of castration-relapse prostate cancer. Stable HNF4α knockdown not only could promote cell proliferation and suppress doxorubicin (Dox)-induced cellular senescence in prostate cancer cells, but also confer resistance to paclitaxel treatment and enhance colony formation capacity and in vivo tumorigenicity of prostate cancer cells. On the contrary, ectopic overexpression of HNF4α could significantly inhibit the cell proliferation of prostate cancer cells, induce cell-cycle arrest at G 2 /M phase and trigger the cellular senescence in prostate cancer cells by activation of p21 signal pathway in a p53-independent manner via its direct transactivation of CDKN1A . Together, our results show that HNF4α performs a tumor suppressor function in prostate cancer via a mechanism of p21-driven cellular senescence.
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-019-1080-3
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2008404-3
    detail.hit.zdb_id: 639046-8
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  • 6
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    Correction: Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
    Springer Science and Business Media LLC ; 2020
    In:  Oncogene Vol. 39, No. 39 ( 2020-09-24), p. 6263-6263
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 39, No. 39 ( 2020-09-24), p. 6263-6263
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-020-1290-8
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2008404-3
    detail.hit.zdb_id: 639046-8
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  • 7
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    Abstract 2000: The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2000-2000
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2000-2000
    Abstract: Cumulative studies indicate that there is a small subpopulation of cancer cells present in cancers or solid tumors referred as cancer stem-like cells (CSCs) as they share some common characteristics with stem cells, particularly self-renewal and multipotency, and these CSCs may contribute to the tumor initiation, treatment resistance and relapse. Recent advances also indicate that prostate cancer stem-like cells (PCSCs) may play a critical role in the development of castration-resistant prostate cancer (CRPC) and also its metastasis. Here, we demonstrated using an established CRPC xenograft model (VCaP-CRPC) that both the xenograft tumors and a xenograft-derived cell line contained more PCSC population, which showed higher expression levels of endothelial nitric oxide synthase (eNOS) and elevated intracellular NO production. PCSCs, isolated from prostaspheres derived from prostate cancer cell lines (DU145, LNCaP and VCaP) using a newly developed agar-based non-attachment 3D-culture method, exhibited up-regulation of eNOS and increased intracellular NO levels. Interruption of eNOS signaling by NOS inhibitors and shRNA-knockdown could significantly suppress the sphere formation capability of prostate cancer cells. Exogenous overexpression of eNOS could promote the tumor growth capacity of prostate cancer cells and their metastasis in vivo, while knockdown of eNOS could prevent the tumor growth and metastasis. Combined transcriptome-sequencing analysis and qPCR validation of prostaspheres upon eNOS-knockdown identified some potential targets of eNOS/NO signaling in the PCSC-enriched prostaspheres. In summary, our results suggest that eNOS/NO signaling may play a positive role in the growth regulation of PCSCs and eNOS might be a potential target for advanced prostate cancer. This study is supported by a General Research Fund from the Research Grants Council of Hong Kong (project code 14107617) and an Innovation and Technology Fund (GHP/003/16GD) from the Innovation and Technology Commission of Hong Kong. Citation Format: Weijie Gao, Dinglan Wu, Yuliang Wang, Zhu Wang, Taiyang Ma, Franky Leung Chan. The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2000.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2000
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 8
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    ERR α augments HIF ‐1 signalling by directly interacting with HIF ‐1 α in normoxic and hypoxic prostate cancer cells
    Wiley ; 2014
    In:  The Journal of Pathology Vol. 233, No. 1 ( 2014-05), p. 61-73
    Details
    In: The Journal of Pathology, Wiley, Vol. 233, No. 1 ( 2014-05), p. 61-73
    Abstract: Adaptation of cancer cells to a hypoxic microenvironment is important for their facilitated malignant growth and advanced development. One major mechanism mediating the hypoxic response involves up‐regulation of hypoxia‐inducible factor 1 ( HIF ‐1) expression, which controls reprogramming of energy metabolism and angiogenesis. Oestrogen‐related receptor‐ α ( ERR α ) is a pivotal regulator of cellular energy metabolism and many biosynthetic pathways, and has also been proposed to be an important factor promoting the Warburg effect in advanced cancer. We and others have previously shown that ERR α expression is increased in prostate cancer and is also a prognostic marker. Here we show that ERR α is oncogenic in prostate cancer and also a key hypoxic growth regulator. ERR α ‐over‐expressing prostate cancer cells were more resistant to hypoxia and showed enhanced HIF ‐1 α protein expression and HIF ‐1 signalling. These effects could also be observed in ERR α ‐over‐expressing cells grown under normoxia, suggesting that ERR α could function to pre‐adapt cancer cells to meet hypoxia stress. Immunoprecipitation and FRET assays indicated that ERR α could physically interact with HIF ‐1 α via its AF ‐2 domain. A ubiquitination assay showed that this ERR α – HIF ‐1 α interaction could inhibit ubiquitination of HIF ‐1 α and thus reduce its degradation. Such ERR α – HIF ‐1 α interaction could be attenuated by XCT790 , an ERR α ‐specific inverse agonist, resulting in reduced HIF ‐1 α levels. In summary, we show that ERR α can promote the hypoxic growth adaptation of prostate cancer cells via a protective interaction with HIF ‐1 α , suggesting ERR α as a potential therapeutic target for cancer treatment. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2014.233.issue-1
    DOI: 10.1002/path.4329
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 3119-7
    detail.hit.zdb_id: 1475280-3
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  • 9
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    Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription
    Springer Science and Business Media LLC ; 2018
    In:  Oncogene Vol. 37, No. 25 ( 2018-6), p. 3340-3355
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 37, No. 25 ( 2018-6), p. 3340-3355
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-018-0198-z
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2008404-3
    detail.hit.zdb_id: 639046-8
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  • 10
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    Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer
    Springer Science and Business Media LLC ; 2021
    In:  Oncogene Vol. 40, No. 15 ( 2021-04-15), p. 2625-2634
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 40, No. 15 ( 2021-04-15), p. 2625-2634
    Abstract: Castration-resistant prostate cancer (CRPC) almost invariably occurs after androgen-deprivation therapy (ADT) for the advanced metastatic disease. It is generally believed that among multiple mechanisms and signaling pathways, CRPC is significantly driven by the reactivation of androgen receptor (AR) signaling in ADT-treated patients with castrate levels of androgen, partially at least mediated by the androgen biosynthesis within the tumor, also known as intratumoral or intraprostatic androgen biosynthesis. Steroidogenic enzymes, such as CYP11A1, CYP17A1, HSD3B1, AKR1C3 and SRD5A, are essential to catalyze the conversion of the initial substrate cholesterol into potent androgens that confers the CRPC progression. Accumulating evidences indicate that many steroidogenic enzymes are upregulated in the progression setting; however, little is known about the dysregulation of these enzymes in CRPC. Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily, of which endogenous physiological ligands are unknown and which are constitutively active independent of any physiological ligands. Studies have validated that besides AR, ONRs could be the potential therapeutic targets for prostate cancer, particularly the lethal CRPC progression. Early studies reveal that ONRs play crucial roles in the transcriptional regulation of steroidogenic enzyme genes. Notably, we and others show that three distinct ONRs, including liver receptor homolog-1 (LRH-1, NR5A2 ), steroidogenic factor 1 (SF-1, AD4BP, NR5A1 ) and estrogen-related receptor α (ERRα, NR3B1 ), can contribute to the CRPC progression by promotion of the intratumoral androgen synthesis via their direct transcriptional regulation on multiple steroidogenic enzymes. This review presents an overview of the current understanding on the intratumoral androgen biosynthesis in CRPC, with a special focus on the emerging roles of ONRs in this process.
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-021-01737-1
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2008404-3
    detail.hit.zdb_id: 639046-8
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