Aberrant mucin-type O-linked glycosylation is a common occurrence in cancer where the upregulation of sialyltransferases is often seen leading to the early termination of O-glycan chains. Mucin-type O-linked glycosylation is not limited to mucins and occurs on many cell surface glycoproteins including EGFR, where the number of sites can be limited. Upon EGF ligation, EGFR induces a signaling cascade and may also translocate to the nucleus where it directly regulates gene transcription, a process modulated by Galectin-3 and MUC1 in some cancers. Here, we show that upon EGF binding, breast cancer cells carrying different O-glycans respond by transcribing different gene expression signatures. MMP10, the principal gene upregulated when cells carrying sialylated core 1 glycans were stimulated with EGF, is also upregulated in ER-positive breast carcinoma reported to express high levels of ST3Gal1 and hence mainly core 1 sialylated O-glycans. In contrast, isogenic cells engineered to carry core 2 glycans upregulate CX3CL1 and FGFBP1 and these genes are upregulated in ER-negative breast carcinomas, also known to express longer core 2 O-glycans. Changes in O-glycosylation did not significantly alter signal transduction downstream of EGFR in core 1 or core 2 O-glycan expressing cells. However, striking changes were observed in the formation of an EGFR/galectin-3/MUC1/β-catenin complex at the cell surface that is present in cells carrying short core 1-based O-glycans but absent in core 2 carrying cells.

中文翻译：

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O-连接粘蛋白型糖基化调节 EGFR 下游的转录程序


异常的粘蛋白型 O-连接糖基化在癌症中很常见，其中唾液酸转移酶的上调经常导致 O-聚糖链的早期终止。粘蛋白型O联糖基化不限于粘蛋白，也发生在包括EGFR在内的许多细胞表面糖蛋白上，但位点数量有限。 EGF 连接后，EGFR 会诱导信号级联反应，并且还可能易位到细胞核，直接调节基因转录，这一过程在某些癌症中由 Galectin-3 和 MUC1 调节。在这里，我们表明，在 EGF 结合后，携带不同 O-聚糖的乳腺癌细胞通过转录不同的基因表达特征做出反应。 MMP10 是携带唾液酸化核心 1 聚糖的细胞受到 EGF 刺激时上调的主要基因，据报道在 ER 阳性乳腺癌中表达高水平的 ST3Gal1，因此主要表达核心 1 唾液酸化 O-聚糖。相比之下，被设计为携带核心 2 聚糖的同基因细胞上调 CX3CL1 和 FGFBP1，并且这些基因在 ER 阴性乳腺癌中上调，也已知表达更长的核心 2 O-聚糖。 O-糖基化的变化并没有显着改变核心 1 或核心 2 O-聚糖表达细胞中 EGFR 下游的信号转导。然而，细胞表面 EGFR/galectin-3/MUC1/β-catenin 复合物的形成发生了显着变化，该复合物存在于携带短核心 1 型 O-聚糖的细胞中，但在携带核心 2 的细胞中不存在。