The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1116424/full |
| _version_ | 1797844275454541824 |
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| author | Veronika M. Metzler Simone de Brot Daisy B. Haigh Corinne L. Woodcock Jennifer Lothion-Roy Anna E. Harris Emeli M. Nilsson Atara Ntekim Jenny L. Persson Jenny L. Persson Brian D. Robinson Francesca Khani Kristian B. Laursen Lorraine J. Gudas Michael S. Toss Srinivasan Madhusudan Emad Rakha David M. Heery Catrin S. Rutland Nigel P. Mongan Nigel P. Mongan Jennie N. Jeyapalan |
| author_facet | Veronika M. Metzler Simone de Brot Daisy B. Haigh Corinne L. Woodcock Jennifer Lothion-Roy Anna E. Harris Emeli M. Nilsson Atara Ntekim Jenny L. Persson Jenny L. Persson Brian D. Robinson Francesca Khani Kristian B. Laursen Lorraine J. Gudas Michael S. Toss Srinivasan Madhusudan Emad Rakha David M. Heery Catrin S. Rutland Nigel P. Mongan Nigel P. Mongan Jennie N. Jeyapalan |
| author_sort | Veronika M. Metzler |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T17:19:39Z |
| format | Article |
| id | doaj.art-a03a643cd6764996be2ac0f2c2df949e |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-09T17:19:39Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-a03a643cd6764996be2ac0f2c2df949e2023-04-19T05:19:24ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-04-011110.3389/fcell.2023.11164241116424The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancerVeronika M. Metzler0Simone de Brot1Daisy B. Haigh2Corinne L. Woodcock3Jennifer Lothion-Roy4Anna E. Harris5Emeli M. Nilsson6Atara Ntekim7Jenny L. Persson8Jenny L. Persson9Brian D. Robinson10Francesca Khani11Kristian B. Laursen12Lorraine J. Gudas13Michael S. Toss14Srinivasan Madhusudan15Emad Rakha16David M. Heery17Catrin S. Rutland18Nigel P. Mongan19Nigel P. Mongan20Jennie N. Jeyapalan21Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomCOMPATH, Institute of Animal Pathology, University of Bern, Bern, SwitzerlandBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomDepartment of Oncology, University Hospital Ibadan, Ibadan, NigeriaDepartment of Molecular Biology, Umeå University, Umeå, SwedenDepartment of Biomedical Sciences, Malmö Universitet, Malmö, SwedenDepartment of Urology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Urology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, Weill Cornell Medicine, New York, NY, United StatesBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomSchool of Pharmacy, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomDepartment of Pharmacology, Weill Cornell Medicine, New York, NY, United StatesBiodiscovery Institute, University of Nottingham, Nottingham, United KingdomHistone 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.https://www.frontiersin.org/articles/10.3389/fcell.2023.1116424/fullepigeneticssplicingtranscriptional regulationKDM-inhibitorshistone modification |
| spellingShingle | Veronika M. Metzler Simone de Brot Daisy B. Haigh Corinne L. Woodcock Jennifer Lothion-Roy Anna E. Harris Emeli M. Nilsson Atara Ntekim Jenny L. Persson Jenny L. Persson Brian D. Robinson Francesca Khani Kristian B. Laursen Lorraine J. Gudas Michael S. Toss Srinivasan Madhusudan Emad Rakha David M. Heery Catrin S. Rutland Nigel P. Mongan Nigel P. Mongan Jennie N. Jeyapalan The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer Frontiers in Cell and Developmental Biology epigenetics splicing transcriptional regulation KDM-inhibitors histone modification |
| title | The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer |
| title_full | The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer |
| title_fullStr | The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer |
| title_full_unstemmed | The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer |
| title_short | The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer |
| title_sort | kdm5b and kdm1a lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer |
| topic | epigenetics splicing transcriptional regulation KDM-inhibitors histone modification |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1116424/full |
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