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Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer

Author

Listed:
  • Thanh Nguyen

    (Washington University in St Louis
    Washington University in St Louis
    Department of Medicine, Baylor College of Medicine)

  • Dhivya Sridaran

    (Washington University in St Louis
    Washington University in St Louis)

  • Surbhi Chouhan

    (Washington University in St Louis
    Washington University in St Louis)

  • Cody Weimholt

    (Washington University in St Louis
    Washington University in St Louis)

  • Audrey Wilson

    (Washington University in St Louis
    Washington University in St Louis)

  • Jingqin Luo

    (Washington University in St Louis)

  • Tiandao Li

    (Washington University at St. Louis)

  • John Koomen

    (Moffitt Cancer Center)

  • Bin Fang

    (Moffitt Cancer Center)

  • Nagireddy Putluri

    (Baylor College of Medicine)

  • Arun Sreekumar

    (Baylor College of Medicine)

  • Felix Y. Feng

    (University of California)

  • Kiran Mahajan

    (Washington University in St Louis
    Washington University in St Louis)

  • Nupam P. Mahajan

    (Washington University in St Louis
    Washington University in St Louis
    Washington University in St Louis)

Abstract

The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy.

Suggested Citation

  • Thanh Nguyen & Dhivya Sridaran & Surbhi Chouhan & Cody Weimholt & Audrey Wilson & Jingqin Luo & Tiandao Li & John Koomen & Bin Fang & Nagireddy Putluri & Arun Sreekumar & Felix Y. Feng & Kiran Mahajan, 2023. "Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38887-7
    DOI: 10.1038/s41467-023-38887-7
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    References listed on IDEAS

    as
    1. Dhivya Sridaran & Surbhi Chouhan & Kiran Mahajan & Arun Renganathan & Cody Weimholt & Shambhavi Bhagwat & Melissa Reimers & Eric H. Kim & Manish K. Thakur & Muhammad A. Saeed & Russell K. Pachynski & , 2022. "Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Bi-Dar Wang & Kristin Ceniccola & SuJin Hwang & Ramez Andrawis & Anelia Horvath & Jennifer A. Freedman & Jacqueline Olender & Stefan Knapp & Travers Ching & Lana Garmire & Vyomesh Patel & Mariano A. G, 2017. "Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    3. Bi-Dar Wang & Kristin Ceniccola & SuJin Hwang & Ramez Andrawis & Anelia Horvath & Jennifer A. Freedman & Jacqueline Olender & Stefan Knapp & Travers Ching & Lana Garmire & Vyomesh Patel & Mariano A. G, 2017. "Correction: Corrigendum: Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-1, December.
    4. Xiangnan Guan & Fanny Polesso & Chaojie Wang & Archana Sehrawat & Reed M. Hawkins & Susan E. Murray & George V. Thomas & Breanna Caruso & Reid F. Thompson & Mary A. Wood & Christina Hipfinger & Scott , 2022. "Androgen receptor activity in T cells limits checkpoint blockade efficacy," Nature, Nature, vol. 606(7915), pages 791-796, June.
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    1. Surbhi Chouhan & Dhivya Sridaran & Cody Weimholt & Jingqin Luo & Tiandao Li & Myles C. Hodgson & Luana N. Santos & Samantha Sommer & Bin Fang & John M. Koomen & Markus Seeliger & Cheng-Kui Qu & Armell, 2024. "SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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