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Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

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Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis Published OnlineFirst March 9, 2010; DOI: 10.1158/0008-5472.CAN-09-3911 Published Online First on March 9, 2010 as 10.1158/0008-5472.CAN-09-3911 Molecular and Cellular Pathobiology Cancer Research Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis Jae-Hyun Park1, Toshihiko Nishidate1, Kyoko Kijima1, Takao Ohashi2, Kaoru Takegawa2, Tomoko Fujikane3, Koichi Hirata3, Yusuke Nakamura1, and Toyomasa Katagiri1,4 Abstract The structure of O-glycosylated proteins is altered in breast cancer cells, but the mechanisms of such an aberrant modification have been largely unknown. We here report critical roles of a novel druggable target, polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6), which is upregulated in a great majority of breast cancers and encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Knockdown of GALNT6 by small interfering RNA significantly enhanced cell adhesion function and suppressed the growth of breast cancer cells. Western blot and immunostaining analyses indicated that wild-type GALNT6 protein could glycosylate and stabilize an oncoprotein mucin 1 (MUC1), which was upregulated with GALNT6 in breast cancer specimens. Furthermore, knockdown of GALNT6 or MUC1 led to similar morphologic changes of cancer cells accompanied by the increase of cell adhesion molecules β-catenin and E-cadherin. Our findings implied that overexpression of GALNT6 might contribute to mammary carcinogenesis through aberrant glycosylation and stabilization of MUC1 and that screening of GALNT6 inhibitors would be valuable for the development of novel therapeutic modalities against breast cancer. Cancer Res; 70(7); OF1–11. ©2010 AACR. Introduction trastuzumab treatment have been recognized as severe adverse events (2). Hence, development of novel molecular- Breast cancer is the most common cancer among women targeted drugs for breast cancer with higher efficacy and low worldwide, and more than a million women are diagnosed risk of adverse reactions is essentially important to improve with breast cancer every year (1). Molecular-targeted drugs clinical management. Toward development of such therapeu- such as tamoxifen, aromatase inhibitors, and trastuzumab tic agents, we had analyzed the genome-wide gene expres- (Herceptin) developed recently have contributed to reduc- sion profile of 81 breast cancers as well as 29 normal tion of its mortality rate and provided a better quality of life human organs using cDNA microarray and have reported to patients with breast tumors expressing estrogen receptor several novel target candidates for breast cancer therapy (ER) or human epidermal growth factor receptor (EGFR) 2 (3–11). In this article, we describe the identification (HER2). However, a significant portion of patients has and characterization of UDP-N-acetyl-α-D-galactosamine no clinical benefit from these treatments. Furthermore, (GalNAc):polypeptide N-acetylgalactosaminyltransferase increases in the risk of endometrial cancer with long-term 6 (GALNT6), which was upregulated in a great majority of tamoxifen administration as well as cardiac toxicity with breast cancer cases. The mucin-type O-glycosylation is initiated by GALNT family members that transfer GalNAc to serine or threonine residues on the target protein (reviewed in ref. 12). This mod- Authors' Affiliations: 1Laboratory of Molecular Medicine, Human Genome ification occurs in the Golgi complex and is presumably con- Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; trolled by the expressions and distributions of GALNT 2Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; 3First Department of Surgery, proteins (13). Interestingly, the structure of glycan chains Sapporo Medical University, Sapporo, Japan; and 4Division of Genome that covalently attached to glycoproteins was altered in Medicine, Institute for Genome Research, The University of Tokushima, breast cancer cells. For instance, the O-glycans were often Tokushima, Japan truncated (core 1–based type) in breast carcinoma cells, Note: Supplementary data for this article are available at Cancer whereas their chains were extended (core 2–based type) in Research Online (http://cancerres.aacrjournals.org/). normal breast cells (reviewed in ref. 14). Mucin 1 (MUC1), Corresponding Author: Yusuke Nakamura, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The a type I transmembrane protein, contributes to mammary University of Tokyo, Minato-ku, Tokyo 108-8639, Japan. Phone: carcinogenesis through interaction with EGFRs, ERα,and 81-3-5449-5372; Fax: 81-3-5449-5433; E-mail: [email protected]. β-catenin (15). These aberrant O-type glycosylations were doi: 10.1158/0008-5472.CAN-09-3911 suggested to regulate the protein stability and subcellular ©2010 American Association for Cancer Research. distribution of MUC1 (16). However, the mechanisms of such www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst March 9, 2010; DOI: 10.1158/0008-5472.CAN-09-3911 Park et al. aberrant O-glycosylation of proteins in breast cancer cells GALNT6 enzyme-dead mutants, which contained a substitu- have been largely unknown. tion at His271 (H271D) or Glu382 (E382Q) that corresponds to Here, we report that GALNT6 transfers GalNAc to MUC1 the residues that are reported to be essential to preserve the protein in vitro and in vivo, stabilizes MUC1 oncoprotein, and enzyme activity of GALNT1 (19), we performed the two-step plays critical roles in proliferation and cytoskeletal regulation mutagenesis PCR (5) using the following primer sets: 5′- of breast cancer cells. GCTCACGTTCCTGGATGCCGACTGTGAGTGCTTCCACGG- 3′ and 5′-CCGTGGAAGCACTCACAGTCGGCATCCAG- Materials and Methods GAACGTGAGC-3′ for H271D and 5′-CAGATGGAGATCTGGG- GAGGGCAGAACGTGGAAATGTCCTTC-3′ and 5′-GAAG‐ Cell lines and clinical samples. Human breast cancer cell GACATTTCCACGTTCTGCCCTCCCCAGATCTCCATCTG-3′ lines (BT-20, HCC1937, MCF7, MDA-MB-231, MDA-MB-435S, for E382Q [underlines indicate nucleotides that were replaced SKBR3, T47D, YMB-1, BT-474, BT-549, HCC1143, HCC1500, from the wild-type (WT)]. HCC1599, MDA-MB-157, MDA-MB-453, OUCB-F, and ZR- Generation of anti–GALNT6-specific antibodies. To 75-1), HBL-100, COS-7, HEK293T, and HeLa cell lines were generate anti-GALNT6 polyclonal antibodies, partial recom- purchased from the American Type Culture Collection binant GALNT6 protein (codons 35–179) was purified and (ATCC) in 2001 to 2003 and cultured under their respective inoculated into rabbits, as described previously (9). In depositors' recommendation. No abnormalities were ob- addition, because of the limited amount of above polyclonal served on the cellular morphology of these cell lines both antibody, we also generated mouse anti-GALNT6 monoclo- at low and high densities of cultures by microscopy accord- nal antibodies, as described previously (20). The hybridomas ing to the guideline from ATCC (17). HBC-4 and HBC-5 cell were subcloned to assess the ability to recognize GALNT6 lines were kindly provided by Dr. Takao Yamori (Division of protein. After limiting dilution, the clones of 3G7 and 4H11 Molecular Pharmacology, Cancer Chemotherapy Center, Jap- were selected for immunostaining and Western blot analyses, anese Foundation for Cancer Research, Tokyo, Japan) with respectively. material transfer agreement in 2001. Human normal breast Recombinant GALNT6 protein. The partial coding epithelial cell lines (HMEC and MCF10A) were purchased sequence of GALNT6 without a signal peptide (codons 35– from Cambrex Bioscience, Inc. in 2007. The stocks of cell 622) was amplified by PCR using the following primer sets: lines that had been deposited in liquid nitrogen were used 5′-ATAAGAATGCGGCCGCAGAGGAGGCCACAGAGAAGCC- in this study. We monitored the cell morphology of these cell 3′ and 5′-CGCGGATCCGACAAAGAGCCACAACTGATG-3′ lines by microscopy and confirmed to maintain their mor- (underlines indicate NotIandBamHI sites, respectively). phologic images in comparison with the original morpholog- The PCR product was cloned into the pQCXIPG-His expres- ic images from the above affiliation. During our recent test in sion vector (Medical and Biological Laboratories). HEK293 2009, no Mycoplasma contamination was detected in cultures cells were transfected with the pQCXIPG-GALNT6-His of all of these cell lines using a Mycoplasma Detection kit vector using FuGENE6 transfection reagent (Roche) and then (Roche). Tissue samples from surgically resected breast can- selected for 2 wk with 2.0 μg/mL puromycin (Invitrogen). cers and their corresponding clinical information were ob- Subsequently, the secreted recombinant GALNT6 protein tained from the First Department of Surgery, Sapporo was purified using Ni-NTA agarose (Qiagen). Medical University (Hokkaido, Japan) and Department of Immunocytochemical staining. The immunocytochemi- Breast Surgery, The Cancer Institute Hospital of Japanese cal staining was performed as described previously (5, 6). Foundation for Cancer Research (Tokyo, Japan) after obtain- Briefly, the cells were incubated with anti-GALNT6 polyclon- ing written informed consents. This study, as well as the use al (diluted at 1:100) or anti-GALNT6 monoclonal antibodies of all clinical materials described above, was approved by in- (3G7, diluted at 1:300), and nuclei were counterstained
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