Cargando…
ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers
The androgen receptor (AR) is a critical transcription factor in prostate cancer (PC) pathogenesis. Its activity in malignant cells is dependent on interactions with a diverse set of co-regulators. These interactions fluctuate depending on androgen availability. For example, the androgen depletion i...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454006/ https://www.ncbi.nlm.nih.gov/pubmed/32885168 http://dx.doi.org/10.1093/narcan/zcaa018 |
_version_ | 1783575447514120192 |
---|---|
author | Kim, Eric H Cao, Dengfeng Mahajan, Nupam P Andriole, Gerald L Mahajan, Kiran |
author_facet | Kim, Eric H Cao, Dengfeng Mahajan, Nupam P Andriole, Gerald L Mahajan, Kiran |
author_sort | Kim, Eric H |
collection | PubMed |
description | The androgen receptor (AR) is a critical transcription factor in prostate cancer (PC) pathogenesis. Its activity in malignant cells is dependent on interactions with a diverse set of co-regulators. These interactions fluctuate depending on androgen availability. For example, the androgen depletion increases the dependence of castration-resistant PCs (CRPCs) on the ACK1 and HOXB13 cell survival pathways. Activated ACK1, an oncogenic tyrosine kinase, phosphorylates cytosolic and nuclear proteins, thereby avoiding the inhibitory growth consequences of androgen depletion. Notably, ACK1-mediated phosphorylation of histone H4, which leads to epigenetic upregulation of AR expression, has emerged as a critical mechanism of CRPC resistance to anti-androgens. This resistance can be targeted using the ACK1-selective small-molecule kinase inhibitor (R)-9b. CRPCs also deploy the bromodomain and extra-terminal domain protein BRD4 to epigenetically increase HOXB13 gene expression, which in turn activates the MYC target genes AURKA/AURKB. HOXB13 also facilitates ligand-independent recruitment of the AR splice variant AR-V7 to chromatin, compensating for the loss of the chromatin remodeling protein, CHD1, and restricting expression of the mitosis control gene HSPB8. These studies highlight the crosstalk between AR–ACK1 and AR–HOXB13 pathways as key mediators of CRPC recurrence. |
format | Online Article Text |
id | pubmed-7454006 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-74540062020-09-01 ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers Kim, Eric H Cao, Dengfeng Mahajan, Nupam P Andriole, Gerald L Mahajan, Kiran NAR Cancer Critical Reviews and Perspectives The androgen receptor (AR) is a critical transcription factor in prostate cancer (PC) pathogenesis. Its activity in malignant cells is dependent on interactions with a diverse set of co-regulators. These interactions fluctuate depending on androgen availability. For example, the androgen depletion increases the dependence of castration-resistant PCs (CRPCs) on the ACK1 and HOXB13 cell survival pathways. Activated ACK1, an oncogenic tyrosine kinase, phosphorylates cytosolic and nuclear proteins, thereby avoiding the inhibitory growth consequences of androgen depletion. Notably, ACK1-mediated phosphorylation of histone H4, which leads to epigenetic upregulation of AR expression, has emerged as a critical mechanism of CRPC resistance to anti-androgens. This resistance can be targeted using the ACK1-selective small-molecule kinase inhibitor (R)-9b. CRPCs also deploy the bromodomain and extra-terminal domain protein BRD4 to epigenetically increase HOXB13 gene expression, which in turn activates the MYC target genes AURKA/AURKB. HOXB13 also facilitates ligand-independent recruitment of the AR splice variant AR-V7 to chromatin, compensating for the loss of the chromatin remodeling protein, CHD1, and restricting expression of the mitosis control gene HSPB8. These studies highlight the crosstalk between AR–ACK1 and AR–HOXB13 pathways as key mediators of CRPC recurrence. Oxford University Press 2020-08-27 /pmc/articles/PMC7454006/ /pubmed/32885168 http://dx.doi.org/10.1093/narcan/zcaa018 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of NAR Cancer. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Critical Reviews and Perspectives Kim, Eric H Cao, Dengfeng Mahajan, Nupam P Andriole, Gerald L Mahajan, Kiran ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers |
title | ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers |
title_full | ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers |
title_fullStr | ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers |
title_full_unstemmed | ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers |
title_short | ACK1–AR and AR–HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers |
title_sort | ack1–ar and ar–hoxb13 signaling axes: epigenetic regulation of lethal prostate cancers |
topic | Critical Reviews and Perspectives |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454006/ https://www.ncbi.nlm.nih.gov/pubmed/32885168 http://dx.doi.org/10.1093/narcan/zcaa018 |
work_keys_str_mv | AT kimerich ack1arandarhoxb13signalingaxesepigeneticregulationoflethalprostatecancers AT caodengfeng ack1arandarhoxb13signalingaxesepigeneticregulationoflethalprostatecancers AT mahajannupamp ack1arandarhoxb13signalingaxesepigeneticregulationoflethalprostatecancers AT andriolegeraldl ack1arandarhoxb13signalingaxesepigeneticregulationoflethalprostatecancers AT mahajankiran ack1arandarhoxb13signalingaxesepigeneticregulationoflethalprostatecancers |