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NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.
Parolia, Abhijit; Eyunni, Sanjana; Verma, Brijesh Kumar; Young, Eleanor; Liu, Yihan; Liu, Lianchao; George, James; Aras, Shweta; Das, Chandan Kanta; Mannan, Rahul; Ur Rasool, Reyaz; Mitchell-Velasquez, Erick; Mahapatra, Somnath; Luo, Jie; Carson, Sandra E; Xiao, Lanbo; Gajjala, Prathibha R; Venkatesh, Sharan; Jaber, Mustapha; Wang, Xiaoju; He, Tongchen; Qiao, Yuanyuan; 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; Asangani, Irfan A.
Affiliation
  • Parolia A; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. aparolia@umich.edu.
  • Eyunni S; Department of Pathology, University of Michigan, Ann Arbor, MI, USA. aparolia@umich.edu.
  • Verma BK; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. aparolia@umich.edu.
  • Young E; Department of Urology, University of Michigan, Ann Arbor, MI, USA. aparolia@umich.edu.
  • Liu Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Liu L; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • George J; Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI, USA.
  • Aras S; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Das CK; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Mannan R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Ur Rasool R; Cancer Biology Program, University of Michigan, Ann Arbor, MI, USA.
  • Mitchell-Velasquez E; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • Mahapatra S; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Luo J; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Carson SE; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Xiao L; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Gajjala PR; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Venkatesh S; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Jaber M; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Wang X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • He T; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Qiao Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Pang M; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Zhang Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Tien JC; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Louw M; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Alhusayan M; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Cao X; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Su F; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Tavana O; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Hou C; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Wang Z; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Ding K; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Chinnaiyan AM; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Asangani IA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Nat Genet ; 2024 Sep 09.
Article in En | MEDLINE | ID: mdl-39251788
ABSTRACT
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 FOXA1AR 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States