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Mol Ther:中国台湾科学家发现HDAC抑制剂治疗乳腺癌新机制

来源:生物谷 2015-01-27 10:12

2015年1月17日讯 /生物谷BIOON/ --近日,国际期刊molecular therapy在线发表了来自中国台湾的研究人员关于HDAC抑制剂治疗乳腺癌的最新进展。

 
HDAC抑制剂(HDACi)是新型临床抗肿瘤药物,这类药物能够抑制HDAC的基因表达并诱导细胞凋亡从而达到控制肿瘤生长的作用。但是,关于此类药物是通过何种机制调控了HDAC下游基因表达并诱导了细胞凋亡仍不清楚。
 
来自中国台湾高雄医科大学的Tsung-Hua Hsieh等人通过研究发现,HDACi能够通过小RNA miR-125a-5p抑制肿瘤发生并诱导人类乳腺癌细胞发生内源性凋亡,而细胞内源性凋亡主要是通过caspase9/3信号途径激活。研究人员通过实验证明,HDACi通过激活RUNX3/p300/HDAC5复合物调节了miR-125a-5p表达,然后miR-125a-5p通过对HDAC5发挥转录后沉默作用,抑制了HDAC5的表达。因此在人类乳腺癌细胞中可能存在由RUNX3信号通路调控的,包含miR-125a-5p和HDAC5的调控环路。
 
综上所述,该文章发现了HDACi影响肿瘤发生和通过下调miR-125a-5p促进细胞凋亡的新机制。这项研究为临床应用HDACi进行肿瘤化疗提供了一些启示。(生物谷Bioon.com)
 
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doi:10.1038/mt.2014.247

HDAC Inhibitors Target HDAC5, Upregulate MicroRNA-125a-5p, and Induce Apoptosis in Breast Cancer Cells
 
Tsung-Hua Hsieh, Chia-Yi Hsu, Cheng-Fang Tsai, Cheng-Yu Long, Chin-Hu Wu, Deng-Chyang Wu, Jau-Nan Lee, Wei-Chun Chang and Eing-Mei Tsai
 
Histone deacetylase inhibitors (HDACi) are novel clinical anticancer drugs that inhibit HDAC gene expression and induce cell apoptosis in human cancers. Nevertheless, the detailed mechanism or the downstream HDAC targets by which HDACi mediates apoptosis in human breast cancer cells remains unclear. Here, we show that HDACi reduce tumorigenesis and induce intrinsic apoptosis of human breast cancer cells through the microRNA miR-125a-5p in vivo and in vitro. Intrinsic apoptosis was activated by the caspase 9/3 signaling pathway. In addition, HDACi mediated the expression of miR-125a-5p by activating RUNX3/p300/HDAC5 complex. Subsequently, miR-125a-5p silenced HDAC5 post-transcriptionally in the cells treated with HDACi. Thus, a regulatory loop may exist in human breast cancer cells involving miR-125a-5p and HDAC5 that is controlled by RUNX3 signaling. Silencing of miR-125a-5p and RUNX3 inhibited cancer progression and activated apoptosis, but silencing of HDAC5 had a converse effect. In conclusion, we demonstrate a possible new mechanism by which HDACi influence tumorigenesis and apoptosis via downregulation of miR-125a-5p expression. This study provides clinical implications in cancer chemotherapy using HDACi.
 
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