NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.
| العنوان: | NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis. |
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| المؤلفون: | Parolia A; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Department of Urology, University of Michigan, Ann Arbor, MI, USA., Eyunni S; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.; Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI, USA.; These authors contributed equally., Verma BK; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; These authors contributed equally., Young E; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Liu L; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., George J; Michigan Center for Translational Pathology, 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; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Mannan R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Rasool RU; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Luo J; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Carson SE; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Mitchell-Velasquez E; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Liu Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Cancer Biology Program, University of Michigan, Ann Arbor, MI, USA., Xiao L; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Gajjala PR; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Jaber M; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Wang X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., He T; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Qiao Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Pang M; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Zhang Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Alhusayan M; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Cao X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA., Tavana O; Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA, USA., Hou C; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., Wang Z; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., Ding K; State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China., Chinnaiyan AM; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Department of Urology, University of Michigan, Ann Arbor, MI, USA.; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA., Asangani IA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 29. Date of Electronic Publication: 2024 Mar 29. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 expression is abnormally gained in prostate cancer cells and its functional inhibition impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites, which is greater than 65% of the AR tumor cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and instead contain the canonical palindromic motifs. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in the physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Concordantly, a dual NSD1/2 PROTAC degrader, called LLC0150, was preferentially cytotoxic in AR-dependent prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo -enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 as viable paralog co-targets in advanced prostate cancer. Competing Interests: Competing interests All the authors declare no competing financial interests. |
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| معلومات مُعتمدة: | R00 CA187664 United States CA NCI NIH HHS; R35 CA231996 United States CA NCI NIH HHS; P30 CA046592 United States CA NCI NIH HHS; K00 CA245825 United States CA NCI NIH HHS; R01 CA249210 United States CA NCI NIH HHS; P50 CA186786 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: AR neo-enhanceosome; AR reprogramming; dual NSD1/2 PROTAC degrader; hormone receptor oncogenesis; targetable paralog co-dependencies |
| تواريخ الأحداث: | Date Created: 20240311 Latest Revision: 20240425 |
| رمز التحديث: | 20240425 |
| مُعرف محوري في PubMed: | PMC10925163 |
| DOI: | 10.1101/2024.02.22.581560 |
| PMID: | 38464251 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.02.22.581560 |
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