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

Abstract

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 determine <i>PLEKHS1</i> promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) and to evaluate if <i>PLEKHS1</i> expression influences clinical outcome. The <i>PLEKHS1</i> promoter mutation was observed in 1/93 of PTCs and none of 18 ATCs in our cohort; however, <i>PLEKHS1</i> expression was aberrantly up-regulated in TCs compared to adjacent non-tumorous thyroid tissues. ATC tumors, an undifferentiated TC, exhibited the highest <i>PLEKHS1</i> expression. In both TCGA and present cohorts of PTCs, <i>PLEKHS1</i> gene methylation density was inversely correlated with its mRNA expression and demethylation at the <i>PLEKHS1</i> locus occurred at two CpGs. Higher <i>PLEKHS1</i> expression was associated with lymph node and distant metastases, and shorter overall and disease-free survival in our cohort of PTC patients. Importantly, <i>PLEKHS1</i> over-expression predicted shorter patient survival in PTCs lacking <i>TERT</i> promoter mutations. Cellular experiments showed that <i>PLEKHS1</i> over-expression enhanced AKT phosphorylation and invasiveness. Collectively, the <i>PLEKHS1</i> gene demethylation causes its over-expression in PTCs. <i>PLEKHS1</i> promotes aggressive behavior of TCs possibly by increasing AKT activity, and its over-expression predicts poor patient outcomes.