HDAC7-mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells
HDAC7-mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells
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DOI：
10.1002/1878-0261.12503
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发表时间：
2019-08-01
影响因子：
6.6
通讯作者：
Brancolini, Claudio
中科院分区：
文献类型：
--
作者：
Cutano, Valentina;Di Giorgio, Eros;Brancolini, Claudio
HDAC 7是一种多效性转录辅助调节因子，控制不同的细胞命运。在这里，我们证明了在人类乳腺上皮细胞中，HDAC 7通过维持一个熟练的微环境来维持细胞增殖并有利于干细胞样细胞群体。特别地，HDAC 7抑制细胞因子和其他环境因子的库，包括胰岛素样生长因子信号传导途径的元件IGFBP 6和IGFBP 7。这种HDAC 7调节的分泌组特征预测管腔A型乳腺癌的阴性预后。ChIP-seq实验显示HDAC 7与基因组局部结合，更频繁地远离转录起始位点。HDAC 7可以与H3 K27乙酰化结构域共定位，并且其缺失进一步增加了转录活性区域的H3 K27 ac。HDAC 7水平在RAS转化的细胞中增加，其中这种蛋白质不仅是增殖和癌症干细胞样细胞生长所需的，而且是侵袭性特征所需的。我们发现HDAC 7的一个重要的直接靶点是IL 24，它足以抑制癌症干细胞样细胞的生长。
HDAC7 is a pleiotropic transcriptional coregulator that controls different cellular fates. Here, we demonstrate that in human mammary epithelial cells, HDAC7 sustains cell proliferation and favours a population of stem-like cells, by maintaining a proficient microenvironment. In particular, HDAC7 represses a repertoire of cytokines and other environmental factors, including elements of the insulin-like growth factor signalling pathway, IGFBP6 and IGFBP7. This HDAC7-regulated secretome signature predicts negative prognosis for luminal A breast cancers. ChIP-seq experiments revealed that HDAC7 binds locally to the genome, more frequently distal from the transcription start site. HDAC7 can colocalize with H3K27-acetylated domains and its deletion further increases H3K27ac at transcriptionally active regions. HDAC7 levels are increased in RAS-transformed cells, in which this protein was required not only for proliferation and cancer stem-like cell growth, but also for invasive features. We show that an important direct target of HDAC7 is IL24, which is sufficient to suppress the growth of cancer stem-like cells.