NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis
Androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to activate malignant phenotypes, the molecular mechanisms of which remain unknown. Here, we show that tumor-specific AR enhancers are critically reliant on H3K36 dimethyltransferase activity of NSD2. NSD2 expression is abnormally induced in prostate cancer, where its inactivation impairs AR transactivation potential by disrupting over 65% of its cistrome. NSD2-dependent AR sites distinctively harbor the chimeric FOXA1:AR half-motif, which exclusively comprise tumor-specific AR enhancer circuitries defined from patient specimens. NSD2 inactivation also engenders increased dependency on the NSD1 paralog, and a dual NSD1/2 PROTAC degrader is preferentially cytotoxic in AR-dependent prostate cancer models. Altogether, we characterize NSD2 as an essential AR neo-enhanceosome subunit that enables its oncogenic activity, and position NSD1/2 as viable co-targets in advanced prostate cancer.
Authors
- Ke Ding (ORCID: https://orcid.org/0000-0001-9016-812X)
- Arul M. Chinnaiyan (ORCID: https://orcid.org/0000-0001-9282-3415)
- Yuanyuan Qiao (ORCID: https://orcid.org/0000-0002-1178-3480)
- James George (ORCID: https://orcid.org/0000-0002-9723-6444)
- Reyaz ur Rasool (ORCID: https://orcid.org/0009-0001-5530-682X)
- Sandra E. Carson (ORCID: https://orcid.org/0000-0002-7716-9627)
- Somnath Mahapatra (ORCID: https://orcid.org/0000-0001-9490-6353)
- Sanjana Eyunni (ORCID: https://orcid.org/0009-0006-5101-6506)
- Xuhong Cao (ORCID: https://orcid.org/0000-0002-2455-3086)
- Abhijit Parolia (ORCID: https://orcid.org/0000-0003-0238-221X)
- Mustapha Jaber (ORCID: https://orcid.org/0009-0003-1632-3154)
- Lianchao Liu
- Rahul Mannan (ORCID: https://orcid.org/0000-0002-6642-0468)
- Eleanor Young (ORCID: https://orcid.org/0000-0001-5393-530X)
- Fengyun Su (ORCID: https://orcid.org/0000-0003-4868-6745)
- Shweta Aras (ORCID: https://orcid.org/0000-0003-2608-1366)
- Tongchen He
- Omid Tavana (ORCID: https://orcid.org/0000-0001-8401-4546)
- Brijesh Kumar Verma (ORCID: https://orcid.org/0000-0003-1870-9715)
- Erick Mitchell-Velasquez (ORCID: https://orcid.org/0000-0003-4093-541X)
- Prathibha R. Gajjala (ORCID: https://orcid.org/0000-0001-5491-4148)
- Irfan A. Asangani (ORCID: https://orcid.org/0000-0001-5381-1702)
- Mohammed Alhusayan (ORCID: https://orcid.org/0000-0002-9488-0752)
- Zhen Wang (ORCID: https://orcid.org/0000-0001-8762-6089)
- Xiaoju Wang (ORCID: https://orcid.org/0000-0002-1800-4902)
- Lanbo Xiao (ORCID: https://orcid.org/0000-0002-1614-8806)
- Chandan Kanta Das
- Jie Luo
- Jean Ching-Yi Tien
- Yuping Zhang (ORCID: https://orcid.org/0009-0007-1481-8101)
- Sharan Venkatesh
- Yihan Liu
- Micheala Louw
- Caiyun Hou
- Matthew Pang
Institutions
- Howard Hughes Medical Institute (US)
- Chinese Academy of Sciences (CN)
- University of Michigan (US)
- Bioscience Research (US)
- Shanghai Institute of Organic Chemistry (CN)
- Michigan Medicine (US)
- Michigan Center for Translational Pathology (US)
- AstraZeneca (United States) (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s41588-024-01893-6
- Citations
- 26
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 10.89
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- National Institutes of Health
- National Cancer Institute