MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators.
MiR137 is an androgen regulated repressor of an extended network of transcriptional coregulators.
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DOI：
10.18632/oncotarget.5958
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
Mongan NP
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文献类型：
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作者：
Nilsson EM;Laursen KB;Whitchurch J;McWilliam A;Ødum N;Persson JL;Heery DM;Gudas LJ;Mongan NP
雄激素和雄激素受体（AR）在男性发育和前列腺癌（PCa）的发病机制和进展中起着至关重要的作用。AR作为配体依赖性转录因子发挥作用，其募集多种酶促不同的表观遗传共调节因子以促进响应雄激素的转录调节。AR辅助调节因子的过度表达与癌症有关。我们已经表明，KDM 1A，AR的辅助调节因子，过度表达，有助于PCa复发，通过促进VEGFA的表达。然而，PCa中AR辅调节因子增加的机制仍然知之甚少。在这项研究中，我们发现microRNA hsa-miR-137（miR 137）肿瘤抑制因子调节转录辅调节因子的扩展网络的表达，包括KDM 1A/LSD 1/AOF 1，KDM 2A/JHDM 1A/FBXL 11，KDM 4A/JMJD 2A，KDM 5 B JARID 1B/PLU 1，KDM 7A/JHDM 1D/PHF 8，MED 1/TRAP 220/DRIP 205和NCoA 2/SRC 2/TIF 2。我们发现，在LnCaP雄激素PCa反应细胞中，雄激素增加了miR 137的表达，并且miR 137位点在雄激素LnCaP：C4-2和PC 3非依赖性PCa细胞中表观遗传学沉默。此外，我们发现miR 137表达的恢复下调了AR靶基因VEGFA的表达，这表明miR 137丢失也在癌症血管生成中发挥作用。最后，我们显示miR 137功能的功能性抑制增强了PSA/KLK 3表达的雄激素诱导。我们的数据表明，miR 137作为雄激素调节抑制剂的雄激素信号通过调节转录辅调节因子的扩展网络的表达。因此，我们认为miR 137的表观遗传沉默是前列腺癌发生和发展过程中促进雄激素信号传导的重要事件。
Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of miR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression.