Resetting cancer stem cell regulatory nodes upon MYC inhibition
Resetting cancer stem cell regulatory nodes upon MYC inhibition
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DOI：
10.15252/embr.201541489
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发表时间：
2016-12-01
期刊：
影响因子：
7.7
通讯作者：
Nasi, Sergio
中科院分区：
文献类型：
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作者：
Galardi, Silvia;Savino, Mauro;Nasi, Sergio
MYC解除管制在人类癌症中很常见，并在维持侵袭性癌症干细胞群中发挥作用。MYC介导广泛的转录反应，控制正常的生物学程序，但其活性尚不清楚。我们以最致命的脑肿瘤胶质母细胞瘤为模型，通过诱导表达MYC衍生多肽干扰MYC活性来研究MYC在癌症干细胞中的功能。Omomyc控制关键的癌干细胞特征，影响肿瘤微环境，抑制血管生成。这是因为Omomyc干扰MYC的正确定位，并且自身与基因组相关联，偏爱MYC占据的位点。这伴随着选择性抑制胶质母细胞瘤干细胞特征的主转录因子，如OLIG2、POU3F2、SOX2，肿瘤抑制和分化效应因子，如ID4、MIAT、PTEN的上调，以及靶向胶质母细胞瘤生长和侵袭的分子，如EGFR和ZEB1的表达调节。数据支持MYC作为网络稳定剂的新观点，它加强了控制细胞表型的基因表达网络的调节节点，并强调Omomyc是靶向癌症干细胞的模型分子。
MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyca MYC-derived polypeptide interfering with MYC activitytaking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC. This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.