MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence
MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence
复制标题
DOI：
10.1074/jbc.m114.624361
复制
发表时间：
2015-04-17
影响因子：
4.8
通讯作者：
Dimri, Goberdhan P.
中科院分区：
文献类型：
--
作者：
Cho, Joon-Ho;Dimri, Manjari;Dimri, Goberdhan P.
背景:组蛋白脱乙酰酶抑制剂(HDACi)抑制polycomb组蛋白的表达,可以调节microrna的表达不同。结果：HDACi上调miR-31的表达，下调BMI1的表达，诱导细胞衰老。结论：miR-31是hdac的新靶点，是细胞衰老的新调控因子。意义：hdac可诱导miR-31， miR-31可导致癌细胞衰老。MicroRNAs （miRNAs）已成为肿瘤发生的重要调节因子。一些mirna，既可以作为肿瘤抑制剂，也可以作为肿瘤抑制mirna，在癌细胞中被解除调控。microRNA-31 （miR-31）已被证明在转移性乳腺癌中过表达。它促进多种致癌表型，包括癌细胞的增殖、运动和侵袭。通过乳腺癌相关的miRNA阵列分析，我们发现miR-31是乳腺癌细胞中组蛋白去乙酰化酶抑制剂（HDACi）的新靶点。具体来说，我们发现丁酸钠（NaB）和panobinostat (LBH589)，两种广谱HDAC抑制剂上调hsa-miR-31 （miR-31）。miR-31的上调伴随着多梳组（PcG）蛋白BMI1的抑制和细胞衰老的诱导。我们进一步表明，抑制miR-31克服了HDACi诱导衰老的作用，恢复了PcG蛋白BMI1的表达。有趣的是，BMI1还作为miR-31转录的抑制因子，表明miR-31和BMI1的表达之间存在交叉负反馈回路。我们的数据表明，miR-31是hdac的重要生理靶点，是与癌症相关的衰老的重要调节因子。这些研究进一步表明，操纵miR-31的表达可用于调节衰老相关的病理状况，如癌症和衰老过程。
Background: Histone deacetylase inhibitor (HDACi) inhibits expression of polycomb group proteins and can differentially regulate expression of miRNAs. Results: HDACi up-regulated expression of miR-31, which down-regulated BMI1 and induced cellular senescence. Conclusion: miR-31 is a novel target of HDACi, and is a novel regulator of cellular senescence. Significance: HDACi can be used to induce miR-31, which in turn can cause senescence in cancer cells.MicroRNAs (miRNAs) have emerged as important regulators of tumorigenesis. Several miRNAs, which can function either as oncomiRs or tumor suppressive miRs are deregulated in cancer cells. The microRNA-31 (miR-31) has been shown to be overexpressed in metastatic breast cancer. It promotes multiple oncogenic phenotypes, including proliferation, motility, and invasion of cancer cells. Using a breast cancer-related miRNA array analysis, we identified miR-31 as a novel target of histone deacetylase inhibitors (HDACi) in breast cancer cells. Specifically, we show that sodium butyrate (NaB) and panobinostat (LBH589), two broad-spectrum HDAC inhibitors up-regulate hsa-miR-31 (miR-31). The up-regulation of miR-31 was accompanied by repression of the polycomb group (PcG) protein BMI1 and induction of cellular senescence. We further show that inhibition of miR-31 overcomes the senescence-inducing effect of HDACi, and restores expression of the PcG protein BMI1. Interestingly, BMI1 also acts as a repressor of miR-31 transcription, suggesting a cross-negative feedback loop between the expression of miR-31 and BMI1. Our data suggest that miR-31 is an important physiological target of HDACi, and that it is an important regulator of senescence relevant to cancer. These studies further suggest that manipulation of miR-31 expression can be used to modulate senescence-related pathological conditions such as cancer, and the aging process.