MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1α/HIF-1β
MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1α/HIF-1β
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DOI：
10.1186/1476-4598-9-108
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发表时间：
2010-05-17
期刊：
影响因子：
37.3
通讯作者：
Sui, Guangchao
中科院分区：
文献类型：
--
作者：
Cao, Paul;Deng, Zhiyong;Sui, Guangchao
背景：在前列腺癌（PCa）中，涉及雄激素消融的常见治疗可暂时缓解疾病，但会导致高度侵袭性和雄激素非依赖性转移性癌症的复发。因此，需要更有效的治疗方法。众所周知，异常的表观遗传学会导致前列腺恶性肿瘤。与基因变化不同，这些表观遗传改变是可逆的，这使得它们成为前列腺癌治疗中阻止癌症进展的有吸引力的目标。作为一种组蛋白甲基转移酶，Ezh2 在表观遗传调控中发挥着重要作用。由于 Ezh2 在 PCa 中过度表达并充当癌基因，因此它已被提议作为 PCa 治疗的真正靶点。 MicroRNA (miRNA) 通过调节蛋白质翻译来调节基因表达。最近，miRNA 在癌症发展中的贡献越来越受到重视。在本报告中，我们的研究表明 microRNA-101 (miR-101) 抑制 Ezh2 表达并差异调节前列腺癌细胞。此外，雄激素处理和 HIF-1 α/HIF-1 β 诱导后，miR-101 的表达发生变化。 结果：在我们的报告基因检测中，miR-101 和 miR-26a 均抑制含有 Ezh2 3'-UTR 的报告基因构建体的表达。当在 PC-3、DU145 和 LNCaP 细胞中异位表达时，miR-101 抑制所有三种细胞系中的内源性 Ezh2 表达，而 miR-26a 仅降低 DU145 中的 Ezh2。异位miR-101降低了PC-3细胞的侵袭能力，而恢复的Ezh2表达则挽救了PC-3细胞的侵袭能力。同样，miR-101 还分别抑制 DU145 和 LNCaP 细胞的细胞侵袭和迁移。有趣的是，异位miR-101对PC-3、DU-145和LNCaP细胞的增殖表现出不同的影响，并且还会引起LNCaP细胞的形态变化。此外，miR-101的表达受雄激素受体和HIF-1α/HIF-1β的调节。虽然甲磺酸去铁胺 (DFO) 诱导的 HIF-1 α/HIF-1 β 降低了 miR-101 水平，但 R-1881 对 miR-101 表达的总体影响是刺激性的。 结论：本研究表明 miR-101 靶向 Ezh2 并降低 PCa 细胞的侵袭性，表明 miR-101 的引入是对抗 PCa 的潜在治疗策略。 MiR-101 差异性调节前列腺细胞增殖。同时，miR-101的表达也在不同的生理条件下受到调节，例如雄激素刺激和HIF-1α/HIF-1β诱导。
Background: In prostate cancer (PCa), the common treatment involving androgen ablation alleviates the disease temporarily, but results in the recurrence of highly aggressive and androgen-independent metastatic cancer. Therefore, more effective therapeutic approaches are needed. It is known that aberrant epigenetics contributes to prostate malignancy. Unlike genetic changes, these epigenetic alterations are reversible, which makes them attractive targets in PCa therapy to impede cancer progression. As a histone methyltransferease, Ezh2 plays an essential role in epigenetic regulation. Since Ezh2 is overexpressed and acts as an oncogene in PCa, it has been proposed as a bona fide target of PCa therapy. MicroRNAs (miRNAs) regulate gene expression through modulating protein translation. Recently, the contribution of miRNAs in cancer development is increasingly appreciated. In this report, we present our study showing that microRNA-101 (miR-101) inhibits Ezh2 expression and differentially regulates prostate cancer cells. In addition, the expression of miR-101 alters upon androgen treatment and HIF-1 alpha/HIF-1 beta induction.Result: In our reporter assays, both miR-101 and miR-26a inhibit the expression of a reporter construct containing the 3'-UTR of Ezh2. When ectopically expressed in PC-3, DU145 and LNCaP cells, miR-101 inhibits endogenous Ezh2 expression in all three cell lines, while miR-26a only decreases Ezh2 in DU145. Ectopic miR-101 reduces the invasion ability of PC-3 cells, while restored Ezh2 expression rescues the invasiveness of PC-3 cells. Similarly, miR-101 also inhibits cell invasion and migration of DU145 and LNCaP cells, respectively. Interestingly, ectopic miR-101 exhibits differential effects on the proliferation of PC-3, DU-145 and LNCaP cells and also causes morphological changes of LNCaP cells. In addition, the expression of miR-101 is regulated by androgen receptor and HIF-1 alpha/HIF-1 beta. While HIF-1 alpha/HIF-1 beta induced by deferoxamine mesylate (DFO) decreases miR-101 levels, the overall effects of R-1881 on miR-101 expression are stimulatory.Conclusions: This study indicates that miR-101 targets Ezh2 and decreases the invasiveness of PCa cells, suggesting that miR-101 introduction is a potential therapeutic strategy to combat PCa. MiR-101 differentially regulates prostate cell proliferation. Meanwhile, the expression of miR-101 is also modulated at different physiological conditions, such as androgen stimulation and HIF-1 alpha/HIF-1 beta induction.