Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

Varadha Balaji Venkadakrishnan; Adam G Presser; Richa Singh; Matthew A Booker; Nicole A Traphagen; Kenny Weng; Nathaniel C E Voss; Navin R Mahadevan; Kei Mizuno; Loredana Puca; Osasenaga Idahor; Sheng-Yu Ku; Martin K Bakht; Ashir A Borah; Zachary T Herbert; Michael Y Tolstorukov; David A Barbie; David S Rickman; Myles Brown; Himisha Beltran

doi:10.1038/s41467-024-51156-5

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

Nat Commun. 2024 Aug 8;15(1):6779. doi: 10.1038/s41467-024-51156-5.

Authors

Varadha Balaji Venkadakrishnan^{1

2

3}, Adam G Presser¹, Richa Singh⁴, Matthew A Booker⁵, Nicole A Traphagen¹, Kenny Weng^{1

6}, Nathaniel C E Voss^{1

7}, Navin R Mahadevan^{1

8}, Kei Mizuno¹, Loredana Puca⁹, Osasenaga Idahor^{1

10}, Sheng-Yu Ku^{1

2

3}, Martin K Bakht^{1

2

3}, Ashir A Borah^{3

11

12}, Zachary T Herbert¹³, Michael Y Tolstorukov⁵, David A Barbie¹, David S Rickman⁴, Myles Brown^{1

14}, Himisha Beltran^{15

16

17}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
⁵ Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Boston College, Chestnut Hill, MA, USA.
⁷ Belmont Hill School, Belmont, MA, USA.
⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁰ Harvard University, Cambridge, MA, USA.
¹¹ Department of Urology, University of California at San Francisco, San Francisco, CA, USA.
¹² Arc Institute, Palo Alto, CA, USA.
¹³ Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁴ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁶ Harvard Medical School, Boston, MA, USA. [email protected].
¹⁷ The Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].

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.

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Animals
Cell Differentiation
Cell Line, Tumor
Cell Lineage
Drug Resistance, Neoplasm / genetics
Enhancer of Zeste Homolog 2 Protein* / genetics
Enhancer of Zeste Homolog 2 Protein* / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Male
Mice
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / pathology
Prostatic Neoplasms, Castration-Resistant / drug therapy
Prostatic Neoplasms, Castration-Resistant / genetics
Prostatic Neoplasms, Castration-Resistant / metabolism
Prostatic Neoplasms, Castration-Resistant / pathology

Substances

Enhancer of Zeste Homolog 2 Protein
EZH2 protein, human

Abstract

MeSH terms

Substances

Grants and funding