The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype.
The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype.
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DOI：
10.1158/0008-5472.can-15-2834
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Bellis SL
中科院分区：
文献类型：
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作者：
Schultz MJ;Holdbrooks AT;Chakraborty A;Grizzle WE;Landen CN;Buchsbaum DJ;Conner MG;Arend RC;Yoon KJ;Klug CA;Bullard DC;Kesterson RA;Oliver PG;O'Connor AK;Yoder BK;Bellis SL
将α2 - 6连接的唾液酸添加到底物糖蛋白上的糖基转移酶ST6Gal - I与癌症发生有关，然而，其致病作用的本质仍知之甚少。在此我们表明，ST6Gal - I在卵巢癌和胰腺癌中表达上调，在转移性肿瘤中富集，并与患者生存率降低相关。值得注意的是，癌细胞中ST6Gal - I的上调赋予了标志性的癌症干细胞样细胞（CSC）特征。调节胰腺癌细胞和卵巢癌细胞中ST6Gal - I的表达直接改变了CSC球体生长，并且具有高ST6Gal - I活性的克隆变体在CSC培养中优先存活。从患者腹水或实体瘤中分选出来的具有α2 - 6唾液酸化的原发性卵巢癌细胞呈球体生长，而缺乏α2 - 6唾液酸化的细胞则保持为单细胞并失去活力。ST6Gal - I还促进了对吉西他滨的耐药性，并使稳定耐药的集落得以形成。与配对未处理的肿瘤相比，吉西他滨对患者来源的异种移植肿瘤的治疗使表达ST6Gal - I的细胞富集。ST6Gal - I还增强了肿瘤起始潜能。在极限稀释试验中，ST6Gal - I的敲低抑制了皮下肿瘤的形成，而在化学诱导的肿瘤起始模型中，条件性ST6Gal - I过表达的小鼠表现出增强的肿瘤发生。最后，我们发现ST6Gal - I诱导了关键的肿瘤促进转录因子Sox9和Slug的表达。总之，这项工作强调了一种特定糖基转移酶在驱动CSC状态方面先前未被认识到的作用。
The glycosyltransferase ST6Gal-I which adds α2-6-linked sialic acids to substrate glycoproteins has been implicated in carcinogenesis, however, the nature of its pathogenic role remains poorly understood. Here we show that ST6Gal-I is upregulated in ovarian and pancreatic carcinomas, enriched in metastatic tumors and associated with reduced patient survival. Notably, ST6Gal-I upregulation in cancer cells conferred hallmark cancer stem-like cell (CSC) characteristics. Modulating ST6Gal-I expression in pancreatic and ovarian cancer cells directly altered CSC spheroid growth, and clonal variants with high ST6Gal-I activity preferentially survived in CSC culture. Primary ovarian cancer cells from patient ascites or solid tumors sorted for α2-6 sialylation grew as spheroids, while cells lacking α2-6 sialylation remained as single cells and lost viability. ST6Gal-I also promoted resistance to gemcitabine and enabled the formation of stably-resistant colonies. Gemcitabine treatment of patient-derived xenograft tumors enriched for ST6Gal-I-expressing cells relative to pair-matched untreated tumors. ST6Gal-I also augmented tumor-initiating potential. In limiting dilution assays, subcutaneous tumor formation was inhibited by ST6Gal-I knockdown, whereas in a chemically-induced tumor initiation model, mice with conditional ST6Gal-I overexpression exhibited enhanced tumorigenesis. Lastly, we found that ST6Gal-I induced expression of the key tumor-promoting transcription factors, Sox9 and Slug. Collectively this work highlighted a previously unrecognized role for a specific glycosyltransferase in driving a CSC state.