Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth.
Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth.
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DOI：
10.1038/onc.2011.194
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发表时间：
2011-12-08
期刊：
影响因子：
8
通讯作者：
Hollingsworth, M. A.
中科院分区：
文献类型：
--
作者：
Taniuchi, K.;Cerny, R. L.;Tanouchi, A.;Kohno, K.;Kotani, N.;Honke, K.;Saibara, T.;Hollingsworth, M. A.
关键词：
分泌蛋白和膜结合蛋白的O-连接糖链通过调节免疫反应、炎症和肿瘤的发生，在胰腺癌的发病机制中发挥重要作用。O-糖基化的一个关键方面是蛋白质与丝氨酸和苏氨酸残基上的N-乙酰半乳糖胺糖基化的位置，由UDP-GalNAc：多肽N-乙酰氨基半乳糖转移酶(GalNAc-ts)的底物特异性调节。因此，GalNAc-ts调控O-糖基化蛋白质生物合成的第一步，确定蛋白质上O-糖基化的位置，对于理解正常和癌症相关的O-糖基化是重要的。我们发现，其中一种酶GalNAc-T3在人胰腺癌组织中过表达，抑制GalNAc-T3在体外和体内显著抑制胰腺癌细胞的生长。此外，抑制GalNAc-T3可诱导胰腺癌细胞的凋亡。我们的结果表明GalNAc-T3可能参与了胰腺癌的发生。由于糖基转移酶表达水平的改变，几乎所有类型的癌症都会发生细胞糖基化的修饰。我们报道鸟嘌呤核苷酸结合蛋白，α转导活性多肽1(GNA1)可能是GalNAc-T3的底物蛋白。GalNAc-T3与GNA1的O-糖基化有关，并影响GNA1的亚细胞分布。下调内源性GNA1可显著抑制PDAC细胞的生长/存活。我们的结果提示GalNAc-T3参与O-糖基化蛋白的功能，从而影响胰腺癌细胞的生长和存活。因此，GalNAc-T3底物蛋白可作为胰腺癌治疗的重要靶点。
O-linked glycans of secreted and membrane bound proteins play an important role in the pathogenesis of pancreatic cancer by modulating immune responses, inflammation, and tumorigenesis. A critical aspect of O-glycosylation, the position at which proteins are glycosylated with N-acetyl-galactosamine on serine and threonine residues, is regulated by the substrate specificity of UDP-GalNAc: polypeptide N-acetylgalactosaminyl-transferases (GalNAc-Ts). Thus, GalNAc-Ts regulate the first committed step in O-glycosylated protein biosynthesis, determine sites of O-glycosylation on proteins, and are important for understanding normal and carcinoma-associated O-glycosylation. We have found that one of these enzymes, GalNAc-T3, is overexpressed in human pancreatic cancer tissues, and suppression of GalNAc-T3 significantly attenuates growth of pancreatic cancer cells in vitro and in vivo. In addition, suppression of GalNAc-T3 induces apoptosis of pancreatic cancer cells. Our results indicate that GalNAc-T3 is likely to be involved in pancreatic carcinogenesis. Modification of cellular glycosylation occurs in nearly all types of cancer as a result of alterations in the expression levels of glycosyltransferases. We report guanine nucleotide binding protein, alpha transducing activity polypeptide 1 (GNAT1) as a possible substrate protein of GalNAc-T3. GalNAc-T3 is associated with O-glycosylation of GNAT1, and affects the subcellular distribution of GNAT1. Knocking down endogenous GNAT1 significantly suppresses the growth/survival of PDAC cells. Our results imply that GalNAc-T3 contributes to the function of O-glycosylated proteins and thereby affects the growth and survival of pancreatic cancer cells. Thus, substrate proteins of GalNAc-T3 should serve as important therapeutic targets for pancreatic cancers.
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