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SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis

Author

Listed:
  • Surbhi Chouhan

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

  • Dhivya Sridaran

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

  • Cody Weimholt

    (Washington University in St Louis)

  • Jingqin Luo

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

  • Tiandao Li

    (Washington University in St Louis)

  • Myles C. Hodgson

    (Masonic Medical Research Institute)

  • Luana N. Santos

    (Masonic Medical Research Institute)

  • Samantha Sommer

    (Masonic Medical Research Institute)

  • Bin Fang

    (SRB3)

  • John M. Koomen

    (SRB3)

  • Markus Seeliger

    (Stony Brook University Medical School, BST 7-120)

  • Cheng-Kui Qu

    (Emory University School of Medicine)

  • Armelle Yart

    (UMR 1301-Inserm 5070-CNRS EFS Univ. P. Sabatier)

  • Maria I. Kontaridis

    (Masonic Medical Research Institute
    Harvard Medical School
    Harvard Medical School)

  • 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

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49978-4
    DOI: 10.1038/s41467-024-49978-4
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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.
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