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أعرض في EDS

Aberrant activation of super enhancer and choline metabolism drive antiandrogen therapy resistance in prostate cancer.

التفاصيل البيبلوغرافية
العنوان: Aberrant activation of super enhancer and choline metabolism drive antiandrogen therapy resistance in prostate cancer.
المؤلفون: Wen S; Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, China.; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA., He Y; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA., Wang L; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA., Zhang J; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Scottsdale, AZ, USA., Quan C; Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, China. quancy98@163.com., Niu Y; Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, China. niuyuanjie9317@163.com., Huang H; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. huang.haojie@mayo.edu.; Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. huang.haojie@mayo.edu.; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. huang.haojie@mayo.edu.
المصدر: Oncogene [Oncogene] 2020 Oct; Vol. 39 (42), pp. 6556-6571. Date of Electronic Publication: 2020 Sep 11.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
مواضيع طبية MeSH: Androgen Antagonists/*pharmacology , Choline Kinase/*genetics , Diacylglycerol Cholinephosphotransferase/*genetics , Drug Resistance, Neoplasm/*genetics , Phosphatidylcholines/*biosynthesis , Prostatic Neoplasms, Castration-Resistant/*therapy , Receptors, Androgen/*metabolism, Androgen Antagonists/therapeutic use ; Androgens/metabolism ; Animals ; Benzamides ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Chemotherapy, Adjuvant/methods ; Choline Kinase/metabolism ; Chromatin Immunoprecipitation Sequencing ; Diacylglycerol Cholinephosphotransferase/metabolism ; Drug Resistance, Neoplasm/drug effects ; Enhancer Elements, Genetic ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Mice ; Nitriles ; Phenylthiohydantoin/analogs & derivatives ; Phenylthiohydantoin/pharmacology ; Phenylthiohydantoin/therapeutic use ; Prostate/pathology ; Prostatectomy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/pathology ; RNA, Long Noncoding/genetics ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic ; Xenograft Model Antitumor Assays
مستخلص: Next generation antiandrogens such as enzalutamide (Enz) are effective initially for the treatment of castration-resistant prostate cancer (CRPC). However, the disease often relapses and the underlying mechanisms remain elusive. By performing H3-lysine-27 acetylation (H3K27ac) ChIP-seq in Enz-resistant CRPC cells, we identified a group of super enhancers (SEs) that are abnormally activated in Enz-resistant CRPC cells and associated with enhanced transcription of a subset of tumor promoting genes such as CHPT1, which catalyzes phosphatidylcholine (PtdCho) synthesis and regulates choline metabolism. Increased CHPT1 conferred CRPC resistance to Enz in vitro and in mice. While androgen receptor (AR) primarily binds to a putative CHPT1 enhancer and mediates androgen-dependent expression of CHPT1 gene in Enz-sensitive prostate cancer cells, AR binds to a different enhancer within the CHPT1 SE locus and facilities androgen-independent expression of CHPT1 in Enz-resistant cells. We further identified a long-non coding RNA transcribed at CHPT1 enhancer (also known as enhancer RNA) that binds to the H3K27ac reader BRD4 and participates in regulating CHPT1 SE activity and CHPT1 gene expression. Our findings demonstrate that aberrantly activated SE upregulates CHPT1 expression and confers Enz resistance in CRPC, suggesting that SE-mediated expression of downstream effectors such as CHPT1 can be viable targets to overcome Enz resistance in PCa.
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المشرفين على المادة: 0 (AR protein, human)
0 (Androgen Antagonists)
0 (Androgens)
0 (BRD4 protein, human)
0 (Benzamides)
0 (Cell Cycle Proteins)
0 (Nitriles)
0 (Phosphatidylcholines)
0 (RNA, Long Noncoding)
0 (Receptors, Androgen)
0 (Transcription Factors)
2010-15-3 (Phenylthiohydantoin)
93T0T9GKNU (enzalutamide)
EC 2.7.1.32 (Choline Kinase)
EC 2.7.8.2 (CHPT1 protein, human)
EC 2.7.8.2 (Diacylglycerol Cholinephosphotransferase)
تواريخ الأحداث: Date Created: 20200912 Date Completed: 20201214 Latest Revision: 20220418
رمز التحديث: 20231215
DOI: 10.1038/s41388-020-01456-z
PMID: 32917955
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5594
DOI:10.1038/s41388-020-01456-z