Data from Restoration of Compact Golgi Morphology in Advanced Prostate Cancer Enhances Susceptibility to Galectin-1–Induced Apoptosis by Modifying Mucin <i>O</i>-Glycan Synthesis

Abstract

<div>Abstract<p>Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 <i>N</i>-acetylglucosaminyltransferase-L (C2GnT-L/<i>GCNT1</i>). This property allows androgen-refractory prostate cancer cells to evade galectin-1 (<i>LGALS1</i>)–induced apoptosis, but the mechanism is not known. We have recently reported that Golgi targeting of glycosyltransferases is mediated by golgins: giantin (<i>GOLGB1</i>) for C2GnT-M (<i>GCNT3</i>) and GM130 (<i>GOLGA2</i>)-GRASP65 (<i>GORASP1</i>) or GM130-giantin for core 1 synthase. Here, we show that for Golgi targeting, C2GnT-L also uses giantin exclusively whereas ST3Gal1 uses either giantin or GM130-GRASP65. In addition, the compact Golgi morphology is detected in both androgen-sensitive prostate cancer and normal prostate cells, but fragmented Golgi and mislocalization of C2GnT-L are found in androgen-refractory cells as well as primary prostate tumors (Gleason grade 2–4). Furthermore, failure of giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and C2GnT-L from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of non-muscle myosin IIA (<i>MYH9</i>) motor protein frees up Rab6a GTPase to promote phosphorylation of giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of C2GnT-L. Finally, the Golgi relocation of C2GnT-L in androgen-refractory cells results in their increased susceptibility to galectin-1–induced apoptosis by replacing sialyl-T antigen with polylactosamine.</p><p><b>Implications:</b> This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis. <i>Mol Cancer Res; 12(12); 1704–16. ©2014 AACR</i>.</p></div>