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

Oncogene volume 39, pages 6556–6571 (2020)Cite this article

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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.

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Fig. 1: Aberrant super enhancer (SE) activation in the CHPT1 gene locus in Enz-resistant PCa cells.
Fig. 2: AR positively regulates CHPT1 gene expression.
Fig. 3: CHPT1 is upregulated independent of AR signaling in Enz resistant PCa cells.
Fig. 4: CHPT1 regulates Enz resistance in PCa cells.
Fig. 5: BET and CBP/p300 bromodomain inhibitors disrupt SE and decrease CHPT1 expression.
Fig. 6: CHPT1-eRNA is overexpressed in C4-2-Enz cells and directly interacts with BRD4.
Fig. 7: CHPT1-eRNA promotes CHPT1 expression and Enz resistance via enhancing SE activity.

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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).

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Authors and Affiliations

  1. 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

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Simeng Wen, Yundong He & Haojie Huang

  3. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Liewei Wang

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Scottsdale, AZ, USA

    Jun Zhang

  5. Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Haojie Huang

  6. Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Haojie Huang

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  1. Simeng Wen
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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.

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Correspondence to Changyi Quan, Yuanjie Niu or Haojie Huang.

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The patient sample study was approved by the Mayo Clinic Institutional Review Board. The mouse studies were approved by the IACUC at Mayo Clinic.

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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

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