SHP2 as a Primordial Epigenetic Enzyme Expunges Histone H3 pTyr-54 to Amend Androgen Receptor Homeostasis

Mutations that decrease activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), causes Noonan syndrome with multiple lentigines or NSML (also called LEOPARD syndrome), while the gain-of-function mutations promotes several malignancies. Precisely how a spectrum of maladies ranging from developmental disorders to cancer are regulated by varying a solitary phosphatase activity is not clearly understood. 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 and its target genes. The SANT domain of NCOR was identified as the epigenetic reader for pY54-H3 marks. NSML patients, SHP2 knock-in mice (which develops NSML), as well as 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 promoting tumor growth in prostate cancer patients. Overall design: Chromatin was isolated from (R)-9b and SHP099 inhibitor (0.5 µM, 18h) treated LNCaP cells and ChIP was performed using pY54-H3 antibody, followed by sequencing. In addition, prostates lysates were prepared from ACK1 knockout mouse, wild type mouse, mouse treated with (R)-9b and SHP099 inhibitor. The prostate lysates were subjected to ChIP with pY54-H3 antibody, followed by sequencing