Abstract

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer.

Details

Title
Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes
Author
Venkadakrishnan, Varadha Balaji 1   VIAFID ORCID Logo  ; Presser, Adam G. 2 ; Singh, Richa 3 ; Booker, Matthew A. 4 ; Traphagen, Nicole A. 2 ; Weng, Kenny 5   VIAFID ORCID Logo  ; Voss, Nathaniel C. E. 6 ; Mahadevan, Navin R. 7 ; Mizuno, Kei 2 ; Puca, Loredana 8 ; Idahor, Osasenaga 9 ; Ku, Sheng-Yu 1   VIAFID ORCID Logo  ; Bakht, Martin K. 1   VIAFID ORCID Logo  ; Borah, Ashir A. 10   VIAFID ORCID Logo  ; Herbert, Zachary T. 11 ; Tolstorukov, Michael Y. 4   VIAFID ORCID Logo  ; Barbie, David A. 2 ; Rickman, David S. 3   VIAFID ORCID Logo  ; Brown, Myles 12   VIAFID ORCID Logo  ; Beltran, Himisha 1   VIAFID ORCID Logo 

1  Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); The Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
2  Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
3  Weill Cornell Medicine, Department of Pathology and Laboratory Medicine, New York, USA (GRID:grid.471410.7) (ISNI:0000 0001 2179 7643) 
4  Dana-Farber Cancer Institute, Department of Informatics and Analytics, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
5  Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Boston College, Chestnut Hill, USA (GRID:grid.208226.c) (ISNI:0000 0004 0444 7053) 
6  Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Belmont Hill School, Belmont, USA (GRID:grid.65499.37) 
7  Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Brigham and Women’s Hospital, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
8  Weill Cornell Medicine, Department of Medicine, New York, USA (GRID:grid.471410.7) (ISNI:0000 0001 2179 7643) 
9  Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Harvard University, Cambridge, USA (GRID:grid.38142.3c) (ISNI:0000 0004 1936 754X) 
10  The Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623); University of California at San Francisco, Department of Urology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Arc Institute, Palo Alto, USA (GRID:grid.266102.1) 
11  Dana-Farber Cancer Institute, Molecular Biology Core Facilities, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
12  Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Dana-Farber Cancer Institute, Center for Functional Cancer Epigenetics, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
Pages
6779
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-51156-5
ProQuest document ID
3090746505
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.