Distinct transcription factor interactions drive HOXB13 activity in different stages of prostate cancer
Abstract
HOXB13 is a lineage-specific transcription factor that plays a critical role in initiation and progression of prostate cancer (PCa). While most research has focused on the role of HOXB13 on androgen receptor (AR) activity, here we demonstrate that HOXB13 is frequently expressed in AR-negative tumors and is essential for the proliferation of both AR-positive and -negative PCa models. Strikingly, HOXB13 is remarkably selective and has almost no effect on nonprostatic tissues. Despite this common essentiality in PCa, HOXB13 activity is markedly different in AR-negative stem cell–like tumors, where interactions with the AP-1 change the HOXB13 cistrome and interactome. Yet despite these distinct activities, HOXB13 activity is commonly mediated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction alters chromatin accessibility at HOXB13-binding sites, causing increased proliferation in AR-negative PCa. Overall, this work demonstrates a distinct mechanism of action for HOXB13 and highlights its critical role in AR-negative castration-resistant PCa.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Betul Ersoy-Fazlioglu
Koç University Research Center for Translational Medicine
Shreyas Lingadahalli
Vancouver Prostate Centre
Umut Berkay Altintas
Vancouver Prostate Centre
Ahmet Cingoz
Koç University Research Center for Translational Medicine
Emirhan Tekoglu
Department of Medical Pharmacology, School of Medicine
Ivan Pak Lok Yu
Vancouver Prostate Centre, Mohseni Institute of Urologic Science, University of British Columbia, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada
Meric Dikbas
Vancouver Prostate Centre
Olka Missaghimamaghani
Vancouver Prostate Centre
Kerim Yavuz
Vancouver Prostate Centre
Hans Adomat
Vancouver Prostate Centre
Ibrahim Kulac
Department of Medical Pharmacology, School of Medicine, Koç University
Tunc Morova
Vancouver Prostate Centre
Kevin Xiao
Vancouver Prostate Centre
Martin Gleave
Vancouver Prostate Centre
Ladan Fazli
Vancouver Prostate Centre
Paloma Cejas
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
Artem Cherkasov
Vancouver Prostate Centre
Wilbert Zwart
Michael Christoph Haffner
Division of Clinical Research, Fred Hutchinson Cancer Center
Henry W. Long
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
Colin Collins
Vancouver Prostate Centre
Tugba Bagci-Onder
Koç University Research Center for Translational Medicine
Nathan A. Lack
Vancouver Prostate Centre, Mohseni Institute of Urologic Science, University of British Columbia, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada