Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer.
Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer.
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DOI：
10.1038/srep23642
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发表时间：
2016-03-23
影响因子：
4.6
通讯作者：
Guda K
中科院分区：
文献类型：
--
作者：
Venkitachalam S;Revoredo L;Varadan V;Fecteau RE;Ravi L;Lutterbaugh J;Markowitz SD;Willis JE;Gerken TA;Guda K
异常蛋白糖基化是一种广泛存在于结直肠癌(CRC)的病理改变，其分子基础及其促进肿瘤进展的机制仍很不清楚。我们对一系列患者来源的结直肠癌细胞系(N = 31)和匹配的原发肿瘤组织中的430个糖化相关基因进行了有针对性的重新测序，确定了12个在结肠癌中显著突变的新的糖化相关基因。特别是，我们观察到与结肠N-和核心1-3 O-连接的糖链生物合成有关的基因(B3GNT2、B4GALT2、ST6GALNAC2)突变丰富，约占所测试CRC的16%。对独立的大规模肿瘤组织数据集的分析证实，在结肠癌和其他胃肠癌中，这些基因内的反复突变。对候选野生型和突变型糖基转移酶的系统生化和表型分析表明，这些突变显著改变了结肠癌细胞的蛋白质定位、翻译后修饰、编码酶活性和/或迁移潜力。这些发现表明，糖基转移酶基因的功能有害突变在一定程度上是异常糖基化的基础，并有助于结肠和其他胃肠道恶性肿瘤的分子亚群的发病。
The molecular basis of aberrant protein glycosylation, a pathological alteration widespread in colorectal cancers (CRC), and the mechanisms by which it contributes to tumor progression remain largely unknown. We performed targeted re-sequencing of 430 glycosylation-associated genes in a series of patient-derived CRC cell lines (N = 31) and matched primary tumor tissues, identifying 12 new significantly mutated glycosylation-associated genes in colon cancer. In particular, we observed an enrichment of mutations in genes (B3GNT2, B4GALT2, ST6GALNAC2) involved in the biosynthesis of N- and Cores 1–3 O-linked glycans in the colon, accounting for ~16% of the CRCs tested. Analysis of independent large-scale tumor tissue datasets confirmed recurrent mutations within these genes in colon and other gastrointestinal cancers. Systematic biochemical and phenotypic characterization of the candidate wild-type and mutant glycosyltransferases demonstrated these mutations as either markedly altering protein localization, post-translational modification, encoded enzymatic activities and/or the migratory potential of colon carcinoma cells. These findings suggest that functionally deleterious mutations in glycosyltransferase genes in part underlie aberrant glycosylation, and contribute to the pathogenesis of molecular subsets of colon and other gastrointestinal malignancies.