Staff View: Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice

Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice

The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F...

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Main Authors:	Karan, Dev, Dubey, Seema, Gunewardena, Sumedha, Iczkowski, Kenneth A., Singh, Manohar, Liu, Pengyuan, Poletti, Angelo, Choo, Yeun-Mun, Chen, Hui-Zi, Hamann, Mark T.
Format:	Article
Published:	Wiley 2024
Subjects:	RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Online Access:	http://eprints.um.edu.my/46994/ https://doi.org/10.1002/1878-0261.13637
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id	my.um.eprints.46994
record_format	eprints
spelling	my.um.eprints.469942025-01-09T02:16:54Z http://eprints.um.edu.my/46994/ Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice Karan, Dev Dubey, Seema Gunewardena, Sumedha Iczkowski, Kenneth A. Singh, Manohar Liu, Pengyuan Poletti, Angelo Choo, Yeun-Mun Chen, Hui-Zi Hamann, Mark T. RC0254 Neoplasms. Tumors. Oncology (including Cancer) The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full-length AR (AR-FL), its spliced variant AR-V7, and the AR-regulated prostate-specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA-seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy-resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene. Wiley 2024-08 Article PeerReviewed Karan, Dev and Dubey, Seema and Gunewardena, Sumedha and Iczkowski, Kenneth A. and Singh, Manohar and Liu, Pengyuan and Poletti, Angelo and Choo, Yeun-Mun and Chen, Hui-Zi and Hamann, Mark T. (2024) Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice. Molecular Oncology, 18 (8). pp. 1966-1979. ISSN 1574-7891, DOI https://doi.org/10.1002/1878-0261.13637 <https://doi.org/10.1002/1878-0261.13637>. https://doi.org/10.1002/1878-0261.13637 10.1002/1878-0261.13637
institution	Universiti Malaya
building	UM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaya
content_source	UM Research Repository
url_provider	http://eprints.um.edu.my/
topic	RC0254 Neoplasms. Tumors. Oncology (including Cancer)
spellingShingle	RC0254 Neoplasms. Tumors. Oncology (including Cancer) Karan, Dev Dubey, Seema Gunewardena, Sumedha Iczkowski, Kenneth A. Singh, Manohar Liu, Pengyuan Poletti, Angelo Choo, Yeun-Mun Chen, Hui-Zi Hamann, Mark T. Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice
description	The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full-length AR (AR-FL), its spliced variant AR-V7, and the AR-regulated prostate-specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA-seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy-resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene.
format	Article
author	Karan, Dev Dubey, Seema Gunewardena, Sumedha Iczkowski, Kenneth A. Singh, Manohar Liu, Pengyuan Poletti, Angelo Choo, Yeun-Mun Chen, Hui-Zi Hamann, Mark T.
author_facet	Karan, Dev Dubey, Seema Gunewardena, Sumedha Iczkowski, Kenneth A. Singh, Manohar Liu, Pengyuan Poletti, Angelo Choo, Yeun-Mun Chen, Hui-Zi Hamann, Mark T.
author_sort	Karan, Dev
title	Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice
title_short	Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice
title_full	Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice
title_fullStr	Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice
title_full_unstemmed	Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice
title_sort	manzamine a reduces androgen receptor transcription and synthesis by blocking e2f8-dna interactions and effectively inhibits prostate tumor growth in mice
publisher	Wiley
publishDate	2024
url	http://eprints.um.edu.my/46994/ https://doi.org/10.1002/1878-0261.13637
_version_	1821105750797189120
score	13.244413

Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice

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