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AGO-RIP-Seq鉴定出多梳抑制复合物I成员CBX7是前列腺癌进展过程中miR-375的主要靶标。

Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression.

作者信息

Pickl Julia M A, Tichy Diana, Kuryshev Vladimir Y, Tolstov Yanis, Falkenstein Michael, Schüler Julia, Reidenbach Daniel, Hotz-Wagenblatt Agnes, Kristiansen Glen, Roth Wilfried, Hadaschik Boris, Hohenfellner Markus, Duensing Stefan, Heckmann Doreen, Sültmann Holger

机构信息

Cancer Genome Research Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.

Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

出版信息

Oncotarget. 2016 Sep 13;7(37):59589-59603. doi: 10.18632/oncotarget.10729.

DOI:10.18632/oncotarget.10729
PMID:27449098
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5312160/
Abstract

Prostate cancer is a heterogeneous disease. MiR-375 is a marker for prostate cancer progression, but its cellular function is not characterized. Here, we provide the first comprehensive investigation of miR-375 in prostate cancer. We show that miR-375 is enriched in prostate cancer compared to normal cells. Furthermore, miR-375 enhanced proliferation, migration and invasion in vitro and induced tumor growth and reduced survival in vivo showing that miR-375 has oncogenic properties in prostate cancer. On the molecular level, we provide the targetome and genome-wide transcriptional changes of miR-375 expression by applying a generalized linear model for Ago-RIP-Seq and RNA-Seq, and show that miR-375 is involved in tumorigenic networks and Polycomb regulation. Integration of tissue and gene ontology data prioritized miR-375 targets and identified the tumor suppressor gene CBX7, a member of Polycomb repressive complex 1, as a major miR-375 target. MiR-375-mediated repression of CBX7 was accompanied by increased expression of its homolog CBX8 and activated transcriptional programs linked to malignant progression in prostate cancer cells. Tissue analysis showed association of CBX7 loss with advanced prostate cancer. Our study indicates that miR-375 exerts its tumor-promoting role in prostate cancer by influencing the epigenetic regulation of transcriptional programs through its ability to directly target the Polycomb complex member CBX7.

摘要

前列腺癌是一种异质性疾病。MiR-375是前列腺癌进展的一个标志物，但其细胞功能尚未明确。在此，我们首次对前列腺癌中的MiR-375进行了全面研究。我们发现，与正常细胞相比，MiR-375在前列腺癌中表达富集。此外，MiR-375在体外增强了细胞增殖、迁移和侵袭能力，并在体内诱导肿瘤生长和降低生存率，表明MiR-375在前列腺癌中具有致癌特性。在分子水平上，我们通过应用广义线性模型进行AGO-RIP-Seq和RNA-Seq分析，提供了MiR-375表达的靶标组和全基因组转录变化，并表明MiR-375参与了致瘤网络和多梳调控。整合组织和基因本体数据对MiR-375靶标进行了优先排序，并确定肿瘤抑制基因CBX7（多梳抑制复合体1的成员）是MiR-375的主要靶标。MiR-375介导的对CBX7的抑制伴随着其同源物CBX8表达的增加以及与前列腺癌细胞恶性进展相关的转录程序的激活。组织分析显示CBX7缺失与晚期前列腺癌有关。我们的研究表明，MiR-375通过直接靶向多梳复合体成员CBX7，影响转录程序的表观遗传调控，从而在前列腺癌中发挥促肿瘤作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/5b72f53d57fe/oncotarget-07-59589-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/4b9f5e569bc2/oncotarget-07-59589-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/de5aed023236/oncotarget-07-59589-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/b8b8758479a5/oncotarget-07-59589-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/8f95e5773cbf/oncotarget-07-59589-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/8ec3db2536ad/oncotarget-07-59589-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/c608cfd0a7ae/oncotarget-07-59589-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/5b72f53d57fe/oncotarget-07-59589-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/4b9f5e569bc2/oncotarget-07-59589-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/de5aed023236/oncotarget-07-59589-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/b8b8758479a5/oncotarget-07-59589-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/8f95e5773cbf/oncotarget-07-59589-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/8ec3db2536ad/oncotarget-07-59589-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/c608cfd0a7ae/oncotarget-07-59589-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e3f4/5312160/5b72f53d57fe/oncotarget-07-59589-g007.jpg

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