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ABSTRACT 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. Access

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Cell Rep. 2016;15:599–610. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported in part by the Mayo Clinic Foundation (to HH)

and the National Natural Science Foundation of China (81972654 to SW), Tianjin International Student Science and Technology Activities Launched Project (20160014 to SW), and Tianjin science

and technology commission (18JCZDJC34800 to CQ). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of

Urology, Tianjin Medical University, Tianjin, China Simeng Wen, Changyi Quan & Yuanjie Niu * Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and

Science, Rochester, MN, USA Simeng Wen, Yundong He & Haojie Huang * Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science,

Rochester, MN, USA Liewei Wang * Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Scottsdale, AZ, USA Jun Zhang * Department of Urology, Mayo

Clinic College of Medicine and Science, Rochester, MN, USA Haojie Huang * Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN, USA Haojie Huang Authors *

Simeng Wen View author publications You can also search for this author inPubMed Google Scholar * Yundong He View author publications You can also search for this author inPubMed Google

Scholar * Liewei Wang View author publications You can also search for this author inPubMed Google Scholar * Jun Zhang View author publications You can also search for this author inPubMed 

Google Scholar * Changyi Quan View author publications You can also search for this author inPubMed Google Scholar * Yuanjie Niu View author publications You can also search for this author

inPubMed Google Scholar * Haojie Huang View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS HH, YN, and CQ conceived the study. SW and YH

generated reagents and conducted experiment design and execution, data collection and data analysis. LW and JZ acquired patient specimens and supervised IHC analysis. HH, SW, YN, and CQ

wrote the manuscript. CORRESPONDING AUTHORS Correspondence to Changyi Quan, Yuanjie Niu or Haojie Huang. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no

conflict of interest. ETHICS The patient sample study was approved by the Mayo Clinic Institutional Review Board. The mouse studies were approved by the IACUC at Mayo Clinic. ADDITIONAL

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wen, S., He, Y., Wang, L. _et al._ Aberrant activation of super enhancer and choline metabolism drive antiandrogen therapy resistance in

prostate cancer. _Oncogene_ 39, 6556–6571 (2020). https://doi.org/10.1038/s41388-020-01456-z Download citation * Received: 27 June 2020 * Revised: 20 August 2020 * Accepted: 02 September

2020 * Published: 11 September 2020 * Issue Date: 15 October 2020 * DOI: https://doi.org/10.1038/s41388-020-01456-z SHARE THIS ARTICLE Anyone you share the following link with will be able

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