Prostatic cell-specific regulation of the synthesis of MUC1-associated sialyl Lewis a.
Prostatic cell-specific regulation of the synthesis of MUC1-associated sialyl Lewis a.
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DOI：
10.1371/journal.pone.0057416
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cheng PW
中科院分区：
文献类型：
--
作者：
Chachadi VB;Ali MF;Cheng PW
唾液刘易斯抗原是参与白细胞运输和癌症转移的选择配体。这些选择素配体的生物合成是在内质网蛋白质主干合成后，通过高尔基体中几种糖基转移酶的连续作用发生的。在这项研究中，我们研究了唾液酸刘易斯a （sLea）的合成是如何在前列腺细胞中被调节的，并鉴定了一种携带这种糖基的粘蛋白。我们用组蛋白去乙酰化酶抑制剂、丙戊酸、tricostatin A （TSA）和亚甲基苯胺羟肟酸（SAHA）治疗人前列腺细胞，包括1个正常细胞和3个癌细胞，然后监测sLea的表达。我们发现SAHA能提高正常前列腺RWPE-1细胞中sLea的产生，但对前列腺癌细胞没有作用。利用siRNA技术和共免疫沉淀，我们发现sLea与MUC1相关，并通过共聚焦免疫荧光显微镜和近端结联实验证实了这一点。saha诱导RWPE-1细胞中sLea的产生是由于B3GALT1基因通过乙酰化组蛋白3和组蛋白4的增强而上调。有趣的是，PC3和LNCaP C-81细胞尽管表达高水平的B3GALT1，但不能产生可检测到的sLea。然而，引入MUC1 cDNA后，在这些细胞中产生MUC1相关的sLea。我们得出结论，sLea的合成不仅受糖蛋白肽主链的控制，还受参与sLea合成的糖蛋白特异性糖基转移酶的控制。此外，SAHA在正常前列腺细胞中诱导这种选择素配体可能会对这种药物造成潜在的严重副作用，这种药物最近被美国食品和药物管理局批准。
Sialyl Lewis antigens are selectin ligands involved in leukocyte trafficking and cancer metastasis. Biosynthesis of these selectin ligands occurs by the sequential actions of several glycosyltransferases in the Golgi apparatus following synthesis of the protein backbone in the endoplasmic reticulum. In this study, we examine how the synthesis of sialyl Lewis a (sLea) is regulated in prostatic cells and identify a mucin that carries this glycotope. We treat human prostatic cells including one normal and three cancerous cells with histone deacetylase inhibitors, valproic acid, tricostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA), and then monitor the expression of sLea. We have found that SAHA enhances the production of sLea in normal prostatic RWPE-1 cells but not prostatic cancer cells. Employing siRNA technology and co-immunoprecipitation, we show that the sLea is associated with MUC1, which is confirmed by confocal immunofluorescence microscopy and proximity ligation assay. The SAHA-induced production of sLea in RWPE-1 cells is resulted from upregulation of B3GALT1 gene via enhancement of acetylated histone-3 and histone-4. Interestingly, PC3 and LNCaP C-81 cells do not produce detectable amounts of sLea despite expressing high levels of B3GALT1. However, the MUC1-associated sLea is generated in these cells after introduction of MUC1 cDNA. We conclude that the synthesis of sLea is controlled by not only peptide backbone of the glycoprotein but also glycoprotein-specific glycosyltransferases involved in the synthesis of sLea. Further, the SAHA induction of this selectin ligand in normal prostatic cells may pose a potentially serious side effect of this drug recently approved by the US Food and Drug Administration.
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影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
影响因子：
2.2
作者：
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DOI：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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