PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma

Pleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determinePLEKHS1promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) and to evaluate ifPLEKHS1expression influences clinical outcome. ThePLEKHS1promoter mutation was observed in 1/93 of PTCs and none of 18 ATCs in our cohort; however,PLEKHS1expression was aberrantly up-regulated in TCs compared to adjacent non-tumorous thyroid tissues. ATC tumors, an undifferentiated TC, exhibited the highestPLEKHS1expression. In both TCGA and present cohorts of PTCs,PLEKHS1gene methylation density was inversely correlated with its mRNA expression and demethylation at thePLEKHS1locus occurred at two CpGs. HigherPLEKHS1expression was associated with lymph node and distant metastases, and shorter overall and disease-free survival in our cohort of PTC patients. Importantly,PLEKHS1over-expression predicted shorter patient survival in PTCs lackingTERTpromoter mutations. Cellular experiments showed thatPLEKHS1over-expression enhanced AKT phosphorylation and invasiveness. Collectively, thePLEKHS1gene demethylation causes its over-expression in PTCs.PLEKHS1promotes aggressive behavior of TCs possibly by increasing AKT activity, and its over-expression predicts poor patient outcomes.