NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis
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Published:2024-09-09
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Parolia AbhijitORCID, Eyunni Sanjana, Verma Brijesh Kumar, Young EleanorORCID, Liu Yihan, Liu Lianchao, George JamesORCID, Aras Shweta, Das Chandan Kanta, Mannan RahulORCID, ur Rasool Reyaz, Mitchell-Velasquez Erick, Mahapatra SomnathORCID, Luo Jie, Carson Sandra E.ORCID, Xiao Lanbo, Gajjala Prathibha R., Venkatesh Sharan, Jaber MustaphaORCID, Wang Xiaoju, He Tongchen, Qiao YuanyuanORCID, Pang Matthew, Zhang Yuping, Tien Jean Ching-Yi, Louw Micheala, Alhusayan Mohammed, Cao Xuhong, Su Fengyun, Tavana Omid, Hou Caiyun, Wang Zhen, Ding Ke, Chinnaiyan Arul M.ORCID, Asangani Irfan A.ORCID
Abstract
AbstractAndrogen 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute Prostate Cancer Foundation U.S. Department of Defense U.S. Department of Health & Human Services | National Institutes of Health
Publisher
Springer Science and Business Media LLC
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