MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells.
MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells.
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MYC破坏了癌细胞中的昼夜节律和代谢。
DOI：
10.1016/j.cmet.2015.09.003
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发表时间：
2015-12-01
期刊：
影响因子：
29
通讯作者：
Dang CV
中科院分区：
文献类型：
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作者：
Altman BJ;Hsieh AL;Sengupta A;Krishnanaiah SY;Stine ZE;Walton ZE;Gouw AM;Venkataraman A;Li B;Goraksha-Hicks P;Diskin SJ;Bellovin DI;Simon MC;Rathmell JC;Lazar MA;Maris JM;Felsher DW;Hogenesch JB;Weljie AM;Dang CV
MYC癌基因编码MYC，MYC是一种通过称为E盒（5′-CACGTG-3′）的位点结合基因组的转录因子，其与异二聚体CLOCK-BMAL 1主昼夜节律转录因子的结合位点相同。因此，我们假设异位MYC表达通过解除调节癌细胞中昼夜节律网络的E-box驱动组件来扰乱时钟。我们在此报道，MYC或N-MYC的表达失调通过直接诱导REV-ERBα抑制BMAL 1的表达和振荡来破坏体外分子钟，这可以通过敲低REV-ERB来挽救。REV-ERBα表达预测N-MYC驱动的BMAL 1表达减少的人神经母细胞瘤的临床结局较差，并且神经母细胞瘤细胞系中异位BMAL 1的再表达抑制其克隆形成。此外，异位MYC深刻地改变了葡萄糖代谢的振荡和干扰多巴胺的分解。我们的研究结果表明，致癌转化与昼夜节律和代谢节律紊乱之间存在未知的联系，我们认为这对癌症有利。
The MYC oncogene encodes MYC, a transcription factor that binds the genome through sites termed E-boxes (5′-CACGTG-3′), which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predicts poor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression, and reexpression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further, ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our results demonstrate an unsuspected link between oncogenic transformation and circadian and metabolic dysrhythmia, which we surmise to be advantageous for cancer.