Epigenetic silencing of the sulfate transporter gene DTDST induces sialyl Lewisx expression and accelerates proliferation of colon cancer cells
Epigenetic silencing of the sulfate transporter gene DTDST induces sialyl Lewisx expression and accelerates proliferation of colon cancer cells
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硫酸盐转运蛋白基因DTDST的表观遗传沉默诱导唾液酸Lewisx表达并加速结肠癌细胞增殖
DOI：
10.1158/0008-5472.can-09-2383
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发表时间：
2010
期刊：
影响因子：
11.2
通讯作者：
R.
中科院分区：
文献类型：
--
作者：
Yusa;A.;Miyazaki;K.;Kimura;N.;Izawa;M.;and Kannagi;R.
结肠癌细胞表达碳水化合物决定簇sialyl Lewisx，而它们表现出其硫酸化衍生物sialyl 6-sulfo Lewisx的表达显著降低。相反，正常结肠上皮细胞强烈表达唾液酸6-磺基Lewisx，但它们实际上不表达唾液酸Lewisx。因此，建议在结肠上皮细胞的恶性转化过程中发生受损的硫酸化，并假定其是癌症中唾液酸化Lewisx表达增加的原因。为了阐明癌症中硫酸化受损的分子生物学背景，我们研究了癌组织中6-O-磺基转移酶同工酶、PAPS转移酶和转运蛋白以及细胞膜硫酸盐转运蛋白DTDST的mRNA表达水平。与非恶性上皮细胞相比，癌细胞中DTDST基因的转录最显著降低（P= 0.0000014;n= 20）。大多数培养的结肠癌细胞的DTDST转录减少，当用组蛋白去乙酰化酶抑制剂培养时，DTDST转录恢复。在tet-off诱导型启动子的控制下，DTDST转录的抑制导致唾液酸化Lewisx表达的增加和唾液酸化6-磺基Lewisx表达的减少。出乎意料的是，当DTDST的转录被抑制时，癌细胞的生长速率显著增强。这些结果表明，硫酸盐转运蛋白基因转录的降低是唾液酸6-磺基Lewisx表达降低和唾液酸Lewisx表达增加的主要原因。DTDST表达减少与癌细胞增殖增强密切相关。Cancer Res; 70（10）; 4064-73.©2010 AACR。
Colon cancer cells express the carbohydrate determinant sialyl Lewisx, while they exhibit markedly decreased the expression of its sulfated derivative, sialyl 6-sulfo Lewisx. In contrast, normal colonic epithelial cells strongly express sialyl 6-sulfo Lewisx, but they virtually do not express sialyl Lewisx. Impaired sulfation was therefore suggested to occur during the course of malignant transformation of colonic epithelial cells and was assumed to be responsible for the increased sialyl Lewisxexpression in cancers. To elucidate the molecular biological background of the impaired sulfation in cancers, we studied the expression levels of mRNA for 6-O-sulfotransferase isoenzymes, PAPS synthases and transporters, and a cell membrane sulfate transporter, DTDST, in cancer tissues. The most striking decrease in cancer cells compared with nonmalignant epithelial cells was noted in the transcription of theDTDSTgene (P= 0.0000014;n= 20). Most cultured colon cancer cells had a diminishedDTDSTtranscription, which was restored when cultured with histone deacetylase inhibitors. Suppression ofDTDSTtranscription under the control of a tet-off inducible promoter resulted in increased sialyl Lewisxexpression and reduced sialyl 6-sulfo Lewisxexpression. Unexpectedly, the growth rate of the cancer cells was markedly enhanced when transcription ofDTDSTwas suppressed. These results show that the decrease in the transcription of the sulfate transporter gene is the major cause of decreased expression of sialyl 6-sulfo Lewisxand increased expression of sialyl Lewisxin colon cancers. The results also suggest that the diminishedDTDSTexpression is closely related to enhanced proliferation of cancer cells. Cancer Res; 70(10); 4064–73. ©2010 AACR.