Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression.
Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression.
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DOI：
10.1158/0008-5472.can-12-2968
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发表时间：
2013-02-01
期刊：
影响因子：
11.2
通讯作者：
Rubin MA
中科院分区：
文献类型：
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作者：
Lin PC;Chiu YL;Banerjee S;Park K;Mosquera JM;Giannopoulou E;Alves P;Tewari AK;Gerstein MB;Beltran H;Melnick AM;Elemento O;Demichelis F;Rubin MA
雄激素受体 (AR) 信号在前列腺癌 (PCA) 发病机制中发挥着关键作用。然而，AR 信号传导的调控仍然难以捉摸。即使采用严格的雄激素剥夺疗法，AR 信号仍然持续存在。在这里，我们的数据表明肿瘤抑制 miRNA、miR-31 和 AR 信号传导之间存在复杂的相互作用。我们检查了原发性和转移性 PCA，发现 miR-31 表达由于启动子高甲基化而降低，重要的是，miR-31 表达水平与疾病的侵袭性呈负相关。由于AR和miR-31的表达在细胞系中呈负相关，我们的研究进一步表明miR-31和AR可以相互抑制。 miR-31的上调通过多种机制有效抑制AR表达并抑制体内PCA生长。值得注意的是，我们发现 miR-31 直接将 AR 靶向位于编码区的一个位点，该位点在 PCA 中通常发生突变。此外，miR-31 抑制细胞周期调节因子，包括 E2F1、E2F2、EXO1、FOXM1 和 MCM2。总之，我们的研究结果表明了一种通过 miR-31 表达介导的新型 AR 调节机制。 miR-31 的下调可能会破坏细胞稳态并促进 PCA 的进化和进展。我们为表观遗传治疗提供启示，并支持检测 miR-31 启动子甲基化作为新型生物标志物的临床开发。
Androgen receptor (AR) signaling plays a critical role in prostate cancer (PCA) pathogenesis. Yet, the regulation of AR signaling remains elusive. Even with stringent androgen deprivation therapy, AR signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31 and AR signaling. We examined primary and metastatic PCA and found that miR-31 expression was reduced as a result of promoter hypermethylation and importantly, the levels of miR-31 expression was inversely correlated with the aggressiveness of the disease. As the expression of AR and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and AR could mutually repress each other. Upregulation of miR-31 effectively suppressed AR expression through multiple mechanisms and inhibited PCA growth in vivo. Notably, we found that miR-31 targeted AR directly at a site located in the coding region, which was commonly mutated in PCA. Additionally, miR-31 suppressed cell cycle regulators, including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel AR regulatory mechanism mediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of PCA. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker.