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.
Nature communications. 2024 Jul 04*** epublish ***
Surbhi Chouhan, Dhivya Sridaran, Cody Weimholt, Jingqin Luo, Tiandao Li, Myles C Hodgson, Luana N Santos, Samantha Le Sommer, Bin Fang, John M Koomen, Markus Seeliger, Cheng-Kui Qu, Armelle Yart, Maria I Kontaridis, Kiran Mahajan, Nupam P Mahajan
Department of Surgery, Washington University in St Louis, St Louis, MO, 63110, USA., Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO, 63110, USA., Division of Public Health Sciences, Washington University in St Louis, St Louis, MO, 63110, USA., Bioinformatics Research Core, Center of Regenerative Medicine, Washington University in St Louis, St Louis, MO, 63110, USA., Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, 2150 Bleecker St, Utica, NY, 13501, USA., Moffitt Cancer Center, SRB3, 12902 Magnolia Drive, Tampa, FL, 33612, USA., Department of Pharmacological Sciences, Stony Brook University Medical School, BST 7-120, Stony Brook, NY, 11794-8651, USA., Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, 30322, USA., UMR 1301-Inserm 5070-CNRS EFS Univ. P. Sabatier, 4bis Ave Hubert Curien, 31100, Toulouse, France., Department of Surgery, Washington University in St Louis, St Louis, MO, 63110, USA. .