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The KDM5B and KDM1A...
The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer
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- Metzler, Veronika M. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- de Brot, Simone (författare)
- COMPATH, Institute of Animal Pathology, University of Bern, Bern, Switzerland,Univ Bern, Inst Anim Pathol, COMPATH, Bern, Switzerland.
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- Haigh, Daisy B. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Woodcock, Corinne L. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Lothion-Roy, Jennifer (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Harris, Anna E. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Nilsson, Emeli M. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Ntekim, Atara (författare)
- Department of Oncology, University Hospital Ibadan, Ibadan, Nigeria,Univ Hosp Ibadan, Dept Oncol, Ibadan, Nigeria.
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- Persson, Jenny L., Professor (författare)
- Malmö universitet,Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Department of Biomedical Sciences, Malmö Universitet, Malmö, Sweden,Institutionen för biomedicinsk vetenskap (BMV),Umeå Univ, Dept Mol Biol, Umeå, Sweden.
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- Robinson, Brian D. (författare)
- Department of Urology, Weill Cornell Medicine, NY, New York, United States,Weill Cornell Med, Dept Urol, New York, NY USA.
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- Khani, Francesca (författare)
- Department of Urology, Weill Cornell Medicine, NY, New York, United States,Weill Cornell Med, Dept Urol, New York, NY USA.
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- Laursen, Kristian B. (författare)
- Department of Pharmacology, Weill Cornell Medicine, NY, New York, United States,Weill Cornell Med, Dept Pharmacol, New York, NY 10021 USA.
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- Gudas, Lorraine J. (författare)
- Department of Pharmacology, Weill Cornell Medicine, NY, New York, United States,Weill Cornell Med, Dept Pharmacol, New York, NY 10021 USA.
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- Toss, Michael S. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Madhusudan, Srinivasan (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Rakha, Emad (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Heery, David M. (författare)
- School of Pharmacy, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Sch Pharm, Nottingham, England.
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- Rutland, Catrin S. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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- Mongan, Nigel P. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom; Department of Pharmacology, Weill Cornell Medicine, NY, New York, United States,Univ Nottingham, Biodiscovery Inst, Nottingham, England.;Weill Cornell Med, Dept Pharmacol, New York, NY 10021 USA.
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- Jeyapalan, Jennie N. (författare)
- Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom,Univ Nottingham, Biodiscovery Inst, Nottingham, England.
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Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom Univ Nottingham, Biodiscovery Inst, Nottingham, England (creator_code:org_t)
- Frontiers Media S.A. 2023
- 2023
- Engelska.
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 11
- Relaterad länk:
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https://doi.org/10.3...
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https://umu.diva-por... (primary) (Raw object)
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https://mau.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.3...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- epigenetics
- histone modification
- KDM-inhibitors
- splicing
- transcriptional regulation
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Metzler, Veronik ...
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de Brot, Simone
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Haigh, Daisy B.
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Woodcock, Corinn ...
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Lothion-Roy, Jen ...
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Harris, Anna E.
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visa fler...
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Nilsson, Emeli M ...
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Ntekim, Atara
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Persson, Jenny L ...
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Robinson, Brian ...
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Khani, Francesca
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Laursen, Kristia ...
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Gudas, Lorraine ...
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Toss, Michael S.
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Madhusudan, Srin ...
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Rakha, Emad
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Heery, David M.
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Rutland, Catrin ...
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Mongan, Nigel P.
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Jeyapalan, Jenni ...
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
- Artiklar i publikationen
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Frontiers in Cel ...
- Av lärosätet
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Umeå universitet
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Malmö universitet