Phosphoproteomic dysregulation drives tumor proliferation in Cushing's disease
Asuzu, D. T.; Mullaney, D.; Mandal, D.; Nwokoye, D.; Varghese, S.; Lopez, D. T.; Bhatt, D.; Johnson, K.; Elkahloun, A.; Abdullaev, Z.; Aldape, K.; Maric, D.; Quignon, C.; Malik, N. S.; Steiner, J. P.; Li, Y.; Wray, S.; Nieman, L. K.; Tatsi, C.; Chittiboina, P.
Show abstract
Pituitary adenomas constitute up to 20% of primary brain tumors, yet somatic mutations are only found in 15% of pituitary adenomas. Epigenomic dysregulation has been proposed as a tumorigenic mechanism in pituitary adenomas causing Cushings disease (CD). We created paired datasets of human CD adenomas and en-route margin adult human pituitary glands and assayed their chromatin accessibility, DNA methylation, transcriptomic, proteomic and phospho-proteomic landscapes. In CD adenomas, we found epigenetic reactivation of a neurodevelopmental phosphoprotein program typically lost in the post-natal pituitary gland. CD cells overexpressed PPP1R17, a potent endogenous inhibitor of the ubiquitous protein phosphatase PP2A. Mechanistically, PPP1R17 overexpression in normal murine pituitary cells recapitulated the adenoma phenotype, and PPP1R17-mediated tumorigenesis was reversible using an FDA-approved small molecule PP2A agonist both in-vitro and in-vivo. Our findings highlight aberrant peptide phosphorylation as a targetable mechanism in CD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/679056v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@8542fborg.highwire.dtl.DTLVardef@f09a24org.highwire.dtl.DTLVardef@17bc39org.highwire.dtl.DTLVardef@46630e_HPS_FORMAT_FIGEXP M_FIG C_FIG
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