Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation.
Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation.
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DOI：
10.1371/journal.ppat.1006020
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发表时间：
2016-11
期刊：
影响因子：
6.7
通讯作者：
DeCaprio JA
中科院分区：
文献类型：
--
作者：
Berrios C;Padi M;Keibler MA;Park DE;Molla V;Cheng J;Lee SM;Stephanopoulos G;Quackenbush J;DeCaprio JA
默克尔细胞多瘤病毒(MCPyV)是一种侵袭性极强的皮肤癌--默克尔细胞癌的病原体。MCPyV小肿瘤抗原(ST)是维持MCC所必需的，可以转化正常细胞。为了深入了解MCPyV ST诱导的细胞扰动，我们对可诱导表达ST的正常人成纤维细胞进行了转录组分析。MCPyV ST随着糖酵解基因水平的增加而动态改变细胞转录组，包括单羧酸乳酸转运蛋白SLC16A1(MCT1)。细胞外流量分析显示，乳酸输出增加反映了ST表达细胞有氧糖酵解的增加。MCT1活性的抑制抑制了MCC细胞的生长，并削弱了MCPyV依赖的IMR90细胞转化。核转录因子κB和MYC都被证明可以调节MCT1的表达。虽然MYC是MCT1诱导所必需的，但MCPyV诱导的MCT1水平在NF-κB亚单位RelA被敲除后下降，支持MCPyV和MYC在调节MCT1水平方面的协同作用。几个MCC品系的MYCL和MYCN含量较高，而MYC含量较低。MYCL水平的升高比MYC或MYCN更有效地促进MCC细胞的胞外酸化。我们的结果证明了MCPyV ST对细胞转录组的影响，并揭示了这种转化至少部分依赖于升高的有氧糖酵解。2008年，默克尔细胞多瘤病毒(MCPyV)被证实在大多数默克尔细胞癌(MCC)中呈克隆性整合，MCC是一种罕见但高度侵袭性的皮肤神经内分泌癌。从那时起，研究强调了MCPyV T抗原在促进和维持MCC发生中的作用。特别是，MCPyV小T抗原(ST)在体内和体外都具有致癌活性。我们对MCPyV ST可诱导表达的正常人成纤维细胞进行了转录组分析，观察到代谢途径基因水平的显著变化，特别是那些参与糖酵解的基因。MCT1是一种主要的单羧酸转运蛋白，在ST表达后迅速被诱导，抑制MCT1活性会降低ST的促生长和转化活性。这种致癌的人类多瘤病毒引起的代谢紊乱反映了MCPyV ST的一种有效的转化机制。
Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis. In 2008, Merkel cell polyomavirus (MCPyV) was identified as clonally integrated in a majority of Merkel cell carcinomas (MCC), a rare but highly aggressive neuroendocrine carcinoma of the skin. Since then, studies have highlighted the roles of the MCPyV T antigens in promoting and sustaining MCC oncogenesis. In particular, MCPyV small T antigen (ST) has oncogenic activity in vivo and in vitro. We performed transcriptome analysis of normal human fibroblasts with inducible expression of MCPyV ST and observed significant alterations in levels of metabolic pathway genes, particularly those involved in glycolysis. MCT1, a major monocarboxylate transporter, was rapidly induced following ST expression and inhibition of MCT1 activity reduced the ST growth promoting and transforming activities. The metabolic perturbations induced by this oncogenic human polyomavirus reflect a potent transforming mechanism of MCPyV ST.
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影响因子：
5.4
作者：
Kwun, Hyun Jin;Shuda, Masahiro;Moore, Patrick S.
通讯作者：
Moore, Patrick S.
影响因子：
30.3
作者：
Kwun HJ;Shuda M;Feng H;Camacho CJ;Moore PS;Chang Y
通讯作者：
Chang Y
影响因子：
5.4
作者：
Berrios, Christian;Jung, Joonil;DeCaprio, James A.
通讯作者：
DeCaprio, James A.
DOI：
10.1038/nrmicro2992
发表时间：
2013-04
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/nrd4626
发表时间：
2015-08
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Lin L;Yee SW;Kim RB;Giacomini KM
通讯作者：
Giacomini KM