Aberrant SGK1 Transcription in LNCaP: A Novel Feed-back Mechanism of TGF-beta1 Regulation in Prostate Carcinogenesis

Abstract

SGK1, a serum- and glucocorticoid-inducible kinase implicated in cancer, is regulated by TGF-beta1 and PI3-kinase. In a comparative study of different benign and cancer ous breast and prostate cells, we demonstrate in this study that exon 11 deletion in SGK1 occurs only in LNCaP prostate cancer cells in association with the deficient TGF-beta1 mRNA message and FOXO3A-driven promoter activity. Using protein modeling approaches, we discovered that exon11 deletion in SGK1 could redistribute electrostatic surface potential around the major kinase domain and affect phosphorylation of SGK1 target proteins including FOXO3A. Concordantly, we found that LNCaP cells displayed FOXO3A hyperphosphorylation at the Ser218/321 (a site next to Ser315 with the marked SGK1 preference) along with changes in gene expression profile of TGF-beta relevant reg ulators (such as SMAD2/4, MAD4 and SKIP). Oncomine-interactome analysis further val- idated a possibility of reciprocal TGF-beta1 regulation by its transcriptional target SGK1 through alterations in FOXO/SMAD and steroid hormone nuclear receptor interactions.