Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3.
Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3.
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长非编码RNA DANCR通过表观遗传学沉默TIMP2/3的表达促进前列腺癌的侵袭
DOI：
10.18632/oncotarget.9350
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发表时间：
2016-06-21
期刊：
影响因子：
--
通讯作者：
Guo P
中科院分区：
文献类型：
--
作者：
Jia J;Li F;Tang XS;Xu S;Gao Y;Shi Q;Guo W;Wang X;He D;Guo P
LncRNA DANCR抑制上皮细胞的分化，然而，其在前列腺癌发展中的功能仍然未知。在本研究中，我们发现DANCR在前列腺癌组织和细胞中的表达较正常前列腺组织和细胞增加，并且DANCR促进前列腺癌细胞的体外侵袭和迁移以及裸鼠移植瘤的转移。从机制上讲，我们发现TIMP 2/3，这是前列腺癌的关键转移抑制剂，下调DANCR协同EZH 2通过表观遗传沉默其启动子通过染色质免疫沉淀测定。此外，我们进一步研究了DANCR是否受促进分化的雄激素-雄激素受体（AR）通路的调节，发现DANCR的表达受到雄激素-AR的抑制;此外，DANCR阻碍了TIMP 2/3的上调以及雄激素-AR对侵袭和迁移的抑制。另一方面，有趣的是，我们发现在前列腺癌细胞中，DANCR敲低降低了通过恩杂鲁胺（一种AR抑制剂）治疗对侵袭和迁移的促进作用。综上所述，我们的研究结果表明DANCR通过抑制TIMP 2/3的表达促进前列腺癌的侵袭和转移，提示DANCR可能是预防前列腺癌转移的潜在靶点，敲低DANCR可能减轻AR抑制剂的潜在副作用。
LncRNA DANCR suppresses differentiation of epithelial cells, however, its function in prostate cancer development is still unknown. In the present study, we found the expression of DANCR increases in prostate cancer tissues and cells compared to normal prostate tissues and cells, moreover, DANCR promotes invasion and migration of prostate cancer cells in vitro and metastasis of tumor xenografts in nude mice. Mechanistically, we found that TIMP2/3, which are critical metastasis inhibitor of prostate cancer, were down-regulated by DANCR synergistically with EZH2 through epigenetically silencing their promoter by chromatin immunoprecipitation assay. In addition, we further investigated whether DANCR is regulated by the differentiation-promoting androgen-androgen receptor (AR) pathway and found that DANCR expression is repressed by androgen-AR; furthermore, DANCR impedes the upregulation of TIMP2/3 and the suppression of invasion and migration by androgen-AR. On the other hand, interestingly, we found that in prostate cancer cells DANCR knockdown decreased the promotion of invasion and migration by the treatment of enzalutamide, which is an AR inhibitor. In summary, our results indicate that DANCR promotes prostate cancer invasion and metastasis through repressing the expression of TIMP2/3, and suggest that DANCR could be a potential target for preventing prostate cancer metastasis, and knockdown DANCR may lessen the potential side effect of AR inhibitor.
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影响因子：
64.8
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4.8
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9.7
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