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The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer

Metzler, Veronika M.; de Brot, Simone; Haigh, Daisy B.; Woodcock, Corinne L.; Lothion-Roy, Jennifer; Harris, Anna E.; Nilsson, Emeli M.; Ntekim, Atara; Persson, Jenny L.; Robinson, Brian D.; Khani, Francesca; Laursen, Kristian B.; Gudas, Lorraine J.; Toss, Michael S.; Madhusudan, Srinivasan; Rakha, Emad; Heery, David M.; Rutland, Catrin S.; Mongan, Nigel P.; Jeyapalan, Jennie N.

The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer Thumbnail


Authors

Veronika M. Metzler

Simone de Brot

Daisy B. Haigh

Jennifer Lothion-Roy

Anna E. Harris

Emeli M. Nilsson

Atara Ntekim

Jenny L. Persson

Brian D. Robinson

Francesca Khani

Kristian B. Laursen

Lorraine J. Gudas

Michael S. Toss



Abstract

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.

Citation

Metzler, V. M., de Brot, S., Haigh, D. B., Woodcock, C. L., Lothion-Roy, J., Harris, A. E., Nilsson, E. M., Ntekim, A., Persson, J. L., Robinson, B. D., Khani, F., Laursen, K. B., Gudas, L. J., Toss, M. S., Madhusudan, S., Rakha, E., Heery, D. M., Rutland, C. S., Mongan, N. P., & Jeyapalan, J. N. (2023). The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer. Frontiers in Cell and Developmental Biology, 11, Article 1116424. https://doi.org/10.3389/fcell.2023.1116424

Journal Article Type Article
Acceptance Date Apr 6, 2023
Online Publication Date Apr 19, 2023
Publication Date Jan 1, 2023
Deposit Date Apr 20, 2023
Publicly Available Date Apr 20, 2023
Journal Frontiers in Cell and Developmental Biology
Electronic ISSN 2296-634X
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 11
Article Number 1116424
DOI https://doi.org/10.3389/fcell.2023.1116424
Keywords Epigenetics, splicing, transcriptional regulation, KDM-inhibitors, histone modification
Public URL https://nottingham-repository.worktribe.com/output/19784614
Publisher URL https://www.frontiersin.org/articles/10.3389/fcell.2023.1116424/full

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