The Open UniversitySkip to content
 

Heterochromatin protein 1α mediates development and aggressiveness of neuroendocrine prostate cancer

Ci, Xinpei; Hao, Jun; Dong, Xin; Choi, Stephen Y.C.; Xue, Hui; Wu, Rebecca; Qu, Sifeng; Gout, Peter W.; Zhang, Fang; Haegert, Anne M.; Fazil, Ladan; Crea, Francesco; Ong, Christopher J.; Zoubedi, Amina; He, Housheng H.; Gleave, Martin E.; Collins, Colin C.; Lin, Dong and Wang, Yuzhuo (2018). Heterochromatin protein 1α mediates development and aggressiveness of neuroendocrine prostate cancer. Cancer Research, 78(10) pp. 2691–2704.

Full text available as:
[img]
Preview
PDF (Accepted Manuscript) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (9MB) | Preview
DOI (Digital Object Identifier) Link: https://doi.org/10.1158/0008-5472.CAN-17-3677
Google Scholar: Look up in Google Scholar

Abstract

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathological feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor (AR) and RE1 silencing transcription factor (REST) and enriched the repressive trimethylated histone H3 at Lys9 (H3K9me3) mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management.

Item Type: Journal Item
Copyright Holders: 2018 American Association for Cancer Research.
ISSN: 0008-5472
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 53744
Depositing User: Francesco Crea
Date Deposited: 08 Mar 2018 14:21
Last Modified: 23 May 2019 20:03
URI: http://oro.open.ac.uk/id/eprint/53744
Share this page:

Metrics

Altmetrics from Altmetric

Citations from Dimensions

Download history for this item

These details should be considered as only a guide to the number of downloads performed manually. Algorithmic methods have been applied in an attempt to remove automated downloads from the displayed statistics but no guarantee can be made as to the accuracy of the figures.

Actions (login may be required)

Policies | Disclaimer

© The Open University   contact the OU