IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49978-4.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49978-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-49978-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Peter J. Cook & Bong Gun Ju & Francesca Telese & Xiangting Wang & Christopher K. Glass & Michael G. Rosenfeld, 2009. "Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions," Nature, Nature, vol. 458(7238), pages 591-596, April.
    2. Ying-Nan P. Chen & Matthew J. LaMarche & Ho Man Chan & Peter Fekkes & Jorge Garcia-Fortanet & Michael G. Acker & Brandon Antonakos & Christine Hiu-Tung Chen & Zhouliang Chen & Vesselina G. Cooke & Jas, 2016. "Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases," Nature, Nature, vol. 535(7610), pages 148-152, July.
    3. 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.
    4. 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. "Author Correction: Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-1, December.
    5. Mark A. Dawson & Andrew J. Bannister & Berthold Göttgens & Samuel D. Foster & Till Bartke & Anthony R. Green & Tony Kouzarides, 2009. "JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin," Nature, Nature, vol. 461(7265), pages 819-822, October.
    6. Harihar Basnet & Xue B. Su & Yuliang Tan & Jill Meisenhelder & Daria Merkurjev & Kenneth A. Ohgi & Tony Hunter & Lorraine Pillus & Michael G. Rosenfeld, 2014. "Tyrosine phosphorylation of histone H2A by CK2 regulates transcriptional elongation," Nature, Nature, vol. 516(7530), pages 267-271, December.
    7. 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.
    8. Lei Dong & Wen-Mei Yu & Hong Zheng & Mignon L. Loh & Silvia T. Bunting & Melinda Pauly & Gang Huang & Muxiang Zhou & Hal E. Broxmeyer & David T. Scadden & Cheng-Kui Qu, 2016. "Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment," Nature, Nature, vol. 539(7628), pages 304-308, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Peter G. Miller & Murugappan Sathappa & Jamie A. Moroco & Wei Jiang & Yue Qian & Sumaiya Iqbal & Qi Guo & Andrew O. Giacomelli & Subrata Shaw & Camille Vernier & Besnik Bajrami & Xiaoping Yang & Ceris, 2022. "Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Alicia Villatoro & Vincent Cuminetti & Aurora Bernal & Carlos Torroja & Itziar Cossío & Alberto Benguría & Marc Ferré & Joanna Konieczny & Enrique Vázquez & Andrea Rubio & Peter Utnes & Almudena Tello, 2023. "Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation," Nature Communications, Nature, vol. 14(1), pages 1-28, December.
    3. Takayoshi Shirasaki & Satoshi Yamagoe & Tetsuro Shimakami & Kazuhisa Murai & Ryu Imamura & Kiyo-Aki Ishii & Hiroaki Takayama & Yukako Matsumoto & Natsumi Tajima-Shirasaki & Naoto Nagata & Ryogo Shimiz, 2022. "Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Teklab Gebregiworgis & Yoshihito Kano & Jonathan St-Germain & Nikolina Radulovich & Molly L. Udaskin & Ahmet Mentes & Richard Huang & Betty P. K. Poon & Wenguang He & Ivette Valencia-Sama & Claire M. , 2021. "The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Fenli Shao & Qianqian Liu & Yuyu Zhu & Zhidan Fan & Wenjun Chen & Shijia Liu & Xiaohui Li & Wenjie Guo & Gen-Sheng Feng & Haiguo Yu & Qiang Xu & Yang Sun, 2021. "Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    6. Zhiyong Xu & Chunyi Guo & Qiaoli Ye & Yueli Shi & Yihui Sun & Jie Zhang & Jiaqi Huang & Yizhou Huang & Chunlai Zeng & Xue Zhang & Yuehai Ke & Hongqiang Cheng, 2021. "Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Jessica L. Kelliher & Melissa L. Folkerts & Kaiyuan V. Shen & Wan Song & Kyle Tengler & Clara M. Stiefel & Seong-Ok Lee & Eloise Dray & Weixing Zhao & Brian Koss & Nicholas R. Pannunzio & Justin W. Le, 2024. "Evolved histone tail regulates 53BP1 recruitment at damaged chromatin," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Shiyun Cao & Shoukai Kang & Haibin Mao & Jiayu Yao & Liangcai Gu & Ning Zheng, 2022. "Defining molecular glues with a dual-nanobody cannabidiol sensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Hidehiro Itonaga & Adnan K. Mookhtiar & Sarah M. Greenblatt & Fan Liu & Concepcion Martinez & Daniel Bilbao & Masai Rains & Pierre-Jacques Hamard & Jun Sun & Afoma C. Umeano & Stephanie Duffort & Chua, 2024. "Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    11. Johann-Christoph Jann & Maximilian Mossner & Vladimir Riabov & Eva Altrock & Nanni Schmitt & Johanna Flach & Qingyu Xu & Verena Nowak & Julia Obländer & Iris Palme & Nadine Weimer & Alexander Streuer , 2021. "Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    12. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49978-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.