Department of Biomedical Informatics, MOE Key Lab of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Prostate Cancer Program, Dana-Farber and Harvard Cancer Center, Harvard University, Boston, MA 02115, USA.
Nucleic Acids Res. 2022 Nov 28;50(21):12186-12201. doi: 10.1093/nar/gkac1090.
Despite being a member of the chromodomain helicase DNA-binding protein family, little is known about the exact role of CHD6 in chromatin remodeling or cancer disease. Here we show that CHD6 binds to chromatin to promote broad nucleosome eviction for transcriptional activation of many cancer pathways. By integrating multiple patient cohorts for bioinformatics analysis of over a thousand prostate cancer datasets, we found CHD6 expression elevated in prostate cancer and associated with poor prognosis. Further comprehensive experiments demonstrated that CHD6 regulates oncogenicity of prostate cancer cells and tumor development in a murine xenograft model. ChIP-Seq for CHD6, along with MNase-Seq and RNA-Seq, revealed that CHD6 binds on chromatin to evict nucleosomes from promoters and gene bodies for transcriptional activation of oncogenic pathways. These results demonstrated a key function of CHD6 in evicting nucleosomes from chromatin for transcriptional activation of prostate cancer pathways.
尽管 CHD6 是染色质螺旋酶 DNA 结合蛋白家族的成员之一，但人们对其在染色质重塑或癌症疾病中的确切作用知之甚少。在这里，我们表明 CHD6 与染色质结合，以促进广泛的核小体驱逐，从而激活许多癌症途径的转录。通过整合多个患者队列，对超过一千个前列腺癌数据集进行生物信息学分析，我们发现 CHD6 在前列腺癌中表达升高，并与预后不良相关。进一步的综合实验表明，CHD6 调节前列腺癌细胞的致癌性和在小鼠异种移植模型中的肿瘤发展。CHD6 的 ChIP-Seq 与 MNase-Seq 和 RNA-Seq 一起揭示了 CHD6 结合在染色质上，从启动子和基因体中驱逐核小体，以激活致癌途径的转录。这些结果表明 CHD6 在从染色质中驱逐核小体以激活前列腺癌途径的转录中具有关键作用。
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