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  • 1
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    Abstract 4397: Gli Activation by Steroid Receptors in Prostate and Breast Cancer Cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4397-4397
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4397-4397
    Abstract: Background: The nuclear steroid receptor superfamily encompasses a group of proteins best known for their functions as primary transcription factors that are conditionally active when bound to a ligand. Here, we show that prominent members of this family (androgen receptor [AR], estrogen receptor [ER-α] and glucocorticoid receptor [GR]) have a secondary function of coordinately activating the Gli family of transcription factors. Previously, we found that liganded AR recognizes and binds to Gli2/Gli3 proteins at their Protein Processing Domains. This binding prevents their degradation and stabilizes them in their high molecular weight, transcriptionally-active forms. This interaction bypasses the need for signaling through Hedgehog/Smoothened to stabilize Gli. To determine whether other steroid receptors have this activity, we tested the ability of human ER-α and GR to bind to Gli3 and whether they increased Gli activity in exogenous (293FT) and endogenous breast and prostate cancer cell systems. Methods: Human AR, ER-α or GR expression vectors were co-transfected into 293FT cells along with a myc-tagged Gli3. Protein extracts were tested for co-immunoprecipitation of AR-/ER-/GR-Gli3 complexes. 293FT cells were co-transfected with AR, ER, or GR along with a Gli-reporter vector. Luciferase activity was measured in transfected cells upon treatment with vehicle, R1881 (AR ligand), estradiol (E2-ER ligand); or dexamethasone (dex-GR ligand). LNCaP (express AR), MCF7 (express ER) or LNCaP-AI cells (express GR) were transfected with reporter in the presence or absence of R1881, E2, dex or vehicle and luciferase activity was measured. AR-/ER-Gli3 complexes were detected by in situ proximity ligation assays in prostate cancer or breast cancer cells. The effect of AR or ER-α siRNA knockdown in LNCaP or MCF7 cells on Gli3 protein stability was measured on western blot. Results: Pulldowns of AR, ER or GR co-immunoprecipitates with Gli3. Transfection with AR or ER increased Gli reporter activity in the presence of vehicle but was further increased by R1881 or E2 treatment. Gli reporter activity was unchanged by transfection with GR in the presence of vehicle but the presence of 5 or 10nM of dex tripled this activity. Gli-luciferase activity was significantly increased in R1881-treated LNCaP cells, E2-treated MCF7 cells and in dex-treated LNCaP-AI cells. PLA detected the presence of AR-Gli3 and ER-Gli3 complexes in nuclei of LNCaP and MCF7 cells. AR and ER-α knockdown destabilized Gli3 protein in LNCaP and MCF7 cells. Conclusion: Collectively our results established a secondary function (Gli activation) shared by an important evolutionary spectrum of human steroid receptors (AR, ER, and GR). As Gli is oncogenic and regulates the expression of many growth-related genes, our observations may explain the pro-oncogenic effects of steroid receptors in steroid-dependent tumour systems. Citation Format: Shabnam Massah, Na Li, Sarah Truong, Jane Foo, Gail Prins, Ralph Buttyan. Gli Activation by Steroid Receptors in Prostate and Breast Cancer Cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4397.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4397
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Abstract 4396: Gli, not Androgen Receptor, is the primary driver of prostate cell growth
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4396-4396
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4396-4396
    Abstract: Introduction Hedgehog (Hh) signaling regulates the activity of Gli transcription factors. Gli controls genes needed for development, cell growth and cell motility. Canonical Hh signaling through Smoothened [Smo] suppresses the proteolysis of Gli2 and Gli3, maintaining them in high molecular weight active forms. Previously, we showed that active androgen receptors ([AR] liganded AR full length and AR-V7) recognize and binds Gli3 its Protein Processing Domain. This binding overrides the need for Smo action and provides a means for stabilization and activation of Gli3 in prostate cancer (PCa) cells without Hh. Studies on the effects of AR binding to Gli2 are more challenging because it is expressed at much lower levels than Gli3. Here, we report that AR also affects Gli2 protein stability and show that Gli2, like Gli3, is a driver of PCa cell growth that is overexpressed in castration resistant disease. Method Immunohistochemistry (IHC) using Gli2- and Gli3-specific antibodies was used to assess expression of Gli2 and Gli3 in human PCa tumor microarrays. Western blot were used to identify and quantify levels of active Gli2 and Gli3 in androgen-treated PCa cells (LNCaP, LNCaP-AI, LAPC4). Proximity ligation assays (PLA) was used to visualize in situ and quantify AR-Gli2 complexes in PCa cells. Gli2- and Gli3-specific siRNAs were used to knock down Gli expression in AR+ (LNCaP-AI, LAPC4, 22Rv1) and AR- (PC3) PCa, cells followed by the Gli reporter assay and the cell growth assay. Results IHC outcomes showed that nuclear Gli2 and Gli3 protein expression was significantly higher in castration resistant tumors compared to primary disease. Androgens increased expression of active Gli2 and Gli3 protein expression in PCa cells and stimulated Gli reporter activity. PLA showed the presence of intranuclear complexes of Gli2/Gli3-AR-Full-length in androgen-treated LNCaP and Gli2-AR-V7 complexes in CWR22rv1 cells. Knockdown of Gli2 or Gli3 present significant reduction in Gli transcriptional activity as well as inhibition on growth of both AR+ and AR- PCa cells that were tested. Conclusion AR activity affects Gli2 processing, as it does for Gli3. We can visualize and quantify AR-Gli2/Gli3 complexes in situ in PCa cells. Gli2 suppression, as well as Gli3 suppression, has a profound effect on PCa cell growth but combined suppression has the strongest effects in certain PCa cells. Finally, Gli2 and Gli3 protein expression is elevated in castration resistant disease. Citation Format: Jane Foo, Na Li, Shabnam Massah, Mannan Nouri, Mike Wang, Ralph Buttyan. Gli, not Androgen Receptor, is the primary driver of prostate cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4396.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4396
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    Epigenetic events regulating monoallelic gene expression
    Informa UK Limited ; 2015
    In:  Critical Reviews in Biochemistry and Molecular Biology Vol. 50, No. 4 ( 2015-07-04), p. 337-358
    Details
    In: Critical Reviews in Biochemistry and Molecular Biology, Informa UK Limited, Vol. 50, No. 4 ( 2015-07-04), p. 337-358
    Type of Medium: Online Resource
    ISSN: 1040-9238 , 1549-7798
    URL: Article
    DOI: 10.3109/10409238.2015.1064350
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2015
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    SSG: 12
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  • 4
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    Gli activation by the estrogen receptor in breast cancer cells: Regulation of cancer cell growth by Gli3
    Elsevier BV ; 2021
    In:  Molecular and Cellular Endocrinology Vol. 522 ( 2021-02), p. 111136-
    Details
    In: Molecular and Cellular Endocrinology, Elsevier BV, Vol. 522 ( 2021-02), p. 111136-
    Type of Medium: Online Resource
    ISSN: 0303-7207
    URL: Article
    DOI: 10.1016/j.mce.2020.111136
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 5
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    Abstract 2922: Loss of retinoblastoma protein dysregulates HIF1-mediated genetic programs, and promotes tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2922-2922
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2922-2922
    Abstract: Loss of tumour suppressor proteins, such as the retinoblastoma protein (Rb), results in tumour progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumour that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and its dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role of Rb in HIF1-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22rV1 human prostate cancer cells. DNA microarray analysis revealed that Rb regulates specific chromosomal gene clusters and loss of Rb in conjunction with hypoxia leads to dysregulation of HIF1-regulated genetic programs that promote cell invasion and neuroendocrine differentiation. Gene ontology analysis of the hypoxia-inducible genes sensitive to loss of Rb revealed that a significant portion of these genes are involved in neuroendocrine differentiation (NED), specifically ENO2, KISS1R and HTR5A. ENO2 is the bonafide marker of neuroendocrine differentiation and it's presence is a signature of late stage castrate resistant prostate cancer. Furthermore, we have functional evidence KISS1R is linked to intracellular calcium mobilization in 22RV1 cells. We have demonstrated that increased expression of HIF-regulated genes in response to loss of Rb activates Akt and ERK signaling pathways and promotes neuroendocrine differentiation and invasion. Inhibition of these signaling pathways significantly decreased actin polymerization in LNCaP cells. For the first time, we have established a direct link between hypoxic tumour environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumours to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. Citation Format: Mark Labrecque, Mandeep Takhar, Rebecca J. Nason, Stephanie Santacruz, Kevin Tam, Shabnam Massah, Anne Haegert, Robert Bell, Manuel Altamirano-Dimas, Colin Collins, Frank Lee, Gratien Prefontaine, Michael Cox, Timothy Beischlag. Loss of retinoblastoma protein dysregulates HIF1-mediated genetic programs, and promotes tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2922.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-2922
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
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    Abstract 3079: Characterization of ER-AF2 inhibitors in breast cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3079-3079
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3079-3079
    Abstract: Up to 80% of breast cancers (BCa) rely on the estrogen receptor (ER) for their growth and progression. This dependence on ER has led to many hormonal therapies that target this receptor. However, almost 40% of these cancers will acquire resistance over the course of the treatment period. One potential cause of resistance is mutations in the estrogen binding site (EBS) of ER. As such, there is an increasing need for novel inhibitors that targets ER at a site separate from the EBS. Here, we propose targeting the activation-function (AF2) pocket of ER that is important for cofactor binding and transcription activation. Billions of compounds were screened through an in-silico deep docking method, and potential AF2 inhibitors were then validated in cell-based and biophysical assays. We tested the effect of potential AF2 inhibitors on ER transcriptional activity using luciferase reporter assay in ER-positive T47D-kbluc cells. We then evaluated the effect of molecules on cell viability of ER-positive T47D and ER-negative MDA-MB-231 cells using PrestoBlue assays in order to exclude off-target effects. From these cell-based assays, we identified several inhibitors that effectively reduced transcriptional activity and viability in ER-positive T47D cells at low micromolar concentrations. We conducted PGC-1α peptide displacement assay to confirm their AF2 binding and estradiol displacement assays to exclude any binding to the EBS. Proximity ligation assay (PLA) showed disruption of the interaction between ER and coactivator SRC-3 upon treatment with ER-AF2 inhibitors in T47D cells. Current work focuses on confirming the direct binding between the compounds and recombinant ER-ligand binding domain by various biophysical assays (MST, BLI, and ITC). Future work aims to solve the structure of ER-LBD in a complex with our lead compound by X-ray crystallography. We predict that the use of potent ER-AF2 inhibitors along with current treatments, will provide a novel tactic that can act as a complementary therapeutic to target treatment resistance in ER+ BCa. Citation Format: Jane Foo, Francesco Gentile, Joseph Lee, Helene Morin, Shabnam Massah, Maria Guo, Jason Smith, Fuqiang Ban, Artem Cherkasov, Nada Lallous. Characterization of ER-AF2 inhibitors in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3079.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3079
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Hedgehog in Prostate Cancer Explained
    Impact Journals, LLC ; 2018
    In:  Oncoscience Vol. 5, No. 3-4 ( 2018-04-29), p. 67-68
    Details
    In: Oncoscience, Impact Journals, LLC, Vol. 5, No. 3-4 ( 2018-04-29), p. 67-68
    Type of Medium: Online Resource
    ISSN: 2331-4737
    URL: Issue
    URL: Article
    DOI: 10.18632/oncoscience.v5i3-4
    DOI: 10.18632/oncoscience.405
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2018
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  • 8
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    Localized, Macromolecular Transport for Thin, Adherent, Single Cells Via an Automated, Single Cell Electroporation Biomanipulator
    Institute of Electrical and Electronics Engineers (IEEE) ; 2013
    In:  IEEE Transactions on Biomedical Engineering Vol. 60, No. 11 ( 2013-11), p. 3113-3123
    Details
    In: IEEE Transactions on Biomedical Engineering, Institute of Electrical and Electronics Engineers (IEEE), Vol. 60, No. 11 ( 2013-11), p. 3113-3123
    Type of Medium: Online Resource
    ISSN: 0018-9294 , 1558-2531
    URL: Article
    DOI: 10.1109/TBME.2013.2268387
    RVK:
    XA 48665
    Language: Unknown
    Publisher: Institute of Electrical and Electronics Engineers (IEEE)
    Publication Date: 2013
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  • 9
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    Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression
    Oxford University Press (OUP) ; 2023
    In:  Nucleic Acids Research Vol. 51, No. 1 ( 2023-01-11), p. 99-116
    Details
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 51, No. 1 ( 2023-01-11), p. 99-116
    Abstract: Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.
    Type of Medium: Online Resource
    ISSN: 0305-1048 , 1362-4962
    URL: Article
    DOI: 10.1093/nar/gkac1158
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 10
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    Epigenetic Characterization of the Growth Hormone Gene Identifies SmcHD1 as a Regulator of Autosomal Gene Clusters
    Public Library of Science (PLoS) ; 2014
    In:  PLoS ONE Vol. 9, No. 5 ( 2014-5-12), p. e97535-
    Details
    In: PLoS ONE, Public Library of Science (PLoS), Vol. 9, No. 5 ( 2014-5-12), p. e97535-
    Type of Medium: Online Resource
    ISSN: 1932-6203
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    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2014
    detail.hit.zdb_id: 2267670-3
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