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C1GALT1 Enhances Proliferation of Hepatocellular Carcinoma Cells Via Modulating MET Glycosylation and Dimerization

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C1GALT1 Enhances Proliferation of Hepatocellular Carcinoma Cells Via Modulating MET Glycosylation and Dimerization Published OnlineFirst July 5, 2013; DOI: 10.1158/0008-5472.CAN-13-0869 Cancer Tumor and Stem Cell Biology Research C1GALT1 Enhances Proliferation of Hepatocellular Carcinoma Cells via Modulating MET Glycosylation and Dimerization Yao-Ming Wu1,3, Chiung-Hui Liu2, Miao-Juei Huang2,3, Hong-Shiee Lai1, Po-Huang Lee1, Rey-Heng Hu1, and Min-Chuan Huang2,3 Abstract Altered glycosylation is a hallmark of cancer. The core 1 b1,3-galactosyltransferase (C1GALT1) controls the formation of mucin-type O-glycans, far overlooked and underestimated in cancer. Here, we report that C1GALT1 mRNA and protein are frequently overexpressed in hepatocellular carcinoma tumors compared with nontumor liver tissues, where it correlates with advanced tumor stage, metastasis, and poor survival. Enforced expression of C1GALT1 was sufficient to enhance cell proliferation, whereas RNA interference– mediated silencing of C1GALT1 was sufficient to suppress cell proliferation in vitro and in vivo.Notably, C1GALT1 attenuation also suppressed hepatocyte growth factor (HGF)–mediated phosphorylation of the MET kinase in hepatocellular carcinoma cells, whereas enforced expression of C1GALT1 enhanced MET phosphorylation. MET blockade with PHA665752 inhibited C1GALT1-enhanced cell viability. In support of these results, we found that the expression level of phospho-MET and C1GALT1 were associated in primary hepatocellular carcinoma tissues. Mechanistic investigations showed that MET was decorated with O-glycans, as revealed by binding to Vicia villosa agglutinin and peanut agglutinin. Moreover, C1GALT1 modified the O-glycosylation of MET, enhancing its HGF-induced dimerization and activation. Together, our results indicate that C1GALT1 overexpression in hepatocellular carcinoma activates HGF signaling via modulation of MET O-glycosylation and dimerization, providing new insights into how O-glycosylation drives hepatocellular carcinoma pathogenesis. Cancer Res; 73(17); 5580–90. Ó2013 AACR. Introduction modifications remain poorly understood (4, 5). Thus, elu- Hepatocellular carcinoma is the fifth most common solid cidation of the precise molecular mechanisms underlying tumor and the third leading cause of cancer-related deaths hepatocellular carcinoma progression is of great impor- worldwide (1). Because of late-stage diagnosis and limited tance for developing new reagents to treat this aggressive therapeutic options, the prognosis of patients with hepa- disease. tocellular carcinoma after medical treatments remains dis- Glycosylation is the most common posttranslational mod- fi appointing (2). Diverse posttranslational modifications con- i cation of proteins, and aberrant glycosylation is often trol various properties of proteins and correlate with many observed in cancers (6, 7). Accumulated evidence indicates diseases, including cancer (3). Although comprehensive that alterations in N-linked glycosylation are a hallmark of genomicandproteomicanalyseshaveidentified many key various liver diseases, including hepatocellular carcinoma drivers of hepatocellular carcinoma, the posttranslational (5, 8). For instance, expression of N-acetylglucosaminyltrans- ferase-III and -V is increased in hepatocellular carcinoma (9, 10). An N-glycan profiling study identified novel N-glycan Authors' Affiliations: 1Department of Surgery, National Taiwan University structures in serum as prognostic markers of hepatocellular Hospital; 2Graduate Institute of Anatomy and Cell Biology, National Taiwan carcinoma (11). In addition, a-1,6-fucosyltransferase can gen- 3 University College of Medicine; and Research Center for Developmental erate fucosylated a-fetoprotein (AFP), which provided a more Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan accurate diagnosis of hepatocellular carcinoma from chronic liver diseases (12, 13). However, changes in O-linked glycosyl- Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). ation have been overlooked in the past. The O-glycosylation of proteins is difficult to explore, as consensus amino acid Y.-M. Wu and C.-H. Liu contributed equally to this work. sequences of O-glycosylation remain unclear and effective Corresponding Authors: Min-Chuan Huang, Graduate Institute of Anat- releasing enzymes for O-glycans are not available (14). Recent- omy and Cell Biology, National Taiwan University College of Medicine, No. 1, Sec. 1 Jen-Ai Road, Taipei 100, Taiwan. Phone: 886-2-23123456, ext. ly, a systematic analysis of mucin-type O-linked glycosylation 88177; Fax: 886-2-23915292; E-mail: [email protected]; and Rey- revealed that mucin type O-glycans are decorated not only on Heng Hu, E-mail: [email protected] mucins but on various unexpected proteins, and functions of doi: 10.1158/0008-5472.CAN-13-0869 the O-glycosylation are largely unknown (15). Several lines of Ó2013 American Association for Cancer Research. evidence indicate that O-glycosylation of proteins plays critical 5580 Cancer Res; 73(17) September 1, 2013 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst July 5, 2013; DOI: 10.1158/0008-5472.CAN-13-0869 C1GALT1 in Hepatocellular Carcinoma roles in cancer. O-glycans on major histocompatibility cyanate (FITC)-, and biotinylated VVA were purchased from complex class I–related chain A (MICA) enhance bladder Vector Laboratories. Recombinant EGF, HGF, IGF-I, and tumor metastasis (16), and O-glycosylation of death receptor protein deglycosylation kits were purchased from Sigma. controls apoptotic signaling in several types of cancer (17). PHA665752 was purchased from Tocris Bioscience. Antibo- In addition, our previous study showed that GALNT2, an dies against C1GALT1, glyceraldehyde-3-phosphate dehy- O-glycosyltransferase, regulates EGF receptor activity and drogenase (GAPDH), and IGF-IR (receptor) were purchased cancer behaviors in hepatocellular carcinoma cells (18). There- from Santa Cruz Biotechnology, Inc.. Antibodies against fore, understanding the roles of O-glycosylation in hepatocel- MET pY 1234/5, IGF-IR pY1135/1136, p-AKT, p-ERK1/2, and lular carcinoma may provide novel insights into the patho- ERK1/2 were purchased from Cell Signaling Technology, Inc. genesis of hepatocellular carcinoma. Antibodies against total MET and AKT were purchased from Core 1 b1,3-galactosyltransferase (C1GALT1) is a critical GeneTex, Inc. mucin-type O-glycosyltransferase that is localized in the Golgi apparatus (19, 20). C1GALT1 transfers galactose (Gal) to N- Tissue array and immunohistochemistry acetylgalactosamine (GalNAc) to a serine (Ser) or threonine Paraffin-embedded human hepatocellular carcinoma tissue (Thr) residue (Tn antigen) to form the Galb1-3GalNAca1-Ser/ microarrays were purchased from SuperBioChips and BioMax. Thr structure (T antigen or core 1 structure; ref. 21). The core 1 Arrays were incubated with anti-C1GALT1 monoclonal anti- structure is the precursor for subsequent extension and mat- body (1:200) in 5% bovine serum albumin/PBS and 0.1% uration of mucin-type O-glycans (22). C1GALT1 has been Triton X-100 (Sigma) for 16 hours at 4C. After rinsing twice shown to regulate angiogenesis, thrombopoiesis, and kidney with PBS, SuperSensitive Link-Label IHC Detection System development (23, 24). Although mucin-type O-glycosylation (BioGenex) was used and the specific immunostaining was and C1GALT1 have been shown to play crucial roles in a variety visualized with 3,3-diaminobenzidine liquid substrate system of biologic functions, the expression and role of C1GALT1 in (Sigma). All sections were counterstained with hematoxylin hepatocellular carcinoma remain unclear. Here, we found that (Sigma). C1GALT1 is frequently overexpressed in hepatocellular carci- noma and its expression is associated with poor survival of cDNA synthesis and quantitative real-time PCR hepatocellular carcinoma patients. We therefore hypothesized Total RNA was isolated using TRIzol reagent (Invitrogen) that C1GALT1 can regulate the malignant growth of hepato- according to the manufacturer's protocol. Two micrograms of cellular carcinoma cells and contribute to the pathogenesis of total RNA was used in reverse transcription reaction using the hepatocellular carcinoma. Superscript III First-Strand cDNA Synthesis Kit (Invitrogen). The cDNA was subjected to real-time PCR. Primers for Materials and Methods C1GALT1 were 50-TGGGAGAAAAGGTTGACACC-30 and 50- Human tissue samples CTTTGACGTGTTTGGCCTTT-30. Primers for GAPDH were Postsurgery frozen hepatocellular carcinoma tissues for 50-GACAAGCTTCCCGTTCTCAG-30 and 50-ACAGTCAGCCG- RNA extraction and Western blotting and paraffin-embedded CATCTTCTT-30. Quantitative real-time PCRs were carried out tissue sections were obtained from the National Taiwan Uni- as described previously (18). versity Hospital (Taipei, Taiwan). This study was approved by the Ethical Committees of National Taiwan University Hospi- Transfection tal, and all patients gave informed consent to have their tissues To overexpress C1GALT1, cells were transfected with before collection. pcDNA3.1/C1GALT1/mycHis plasmids using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol. Cell culture Empty pcDNA3.1/mycHis plasmid was used as mock transfec- Human liver cancer cell lines, Huh7, PLC5, Sk-Hep1, and tant. The transfected cells were selected with 600 mg/mL of HepG2, were purchased from Bioresource Collection and G418 for 14 days and then pooled for further studies. Research Center in the year 2008.
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