SOX4 Promotes Proliferative Signals by Regulating Glycolysis through AKT Activation in Melanoma Cells
SOX4 Promotes Proliferative Signals by Regulating Glycolysis through AKT Activation in Melanoma Cells
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SOX4 通过 AKT 激活调节黑色素瘤细胞中的糖酵解来促进增殖信号。
DOI：
10.1016/j.jid.2017.06.026
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发表时间：
2017-11-01
影响因子：
6.5
通讯作者：
Li, Chunying
中科院分区：
文献类型：
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作者：
Dai, Wei;Xu, Xinyuan;Li, Chunying
性别决定区Y相关高迁移率族盒转录因子4（SOX 4）在胚胎发生过程中起着重要作用，并控制细胞的命运和分化。最近，在各种癌症类型中已经报道了增加的SOX 4表达，有助于癌细胞的进展和存活。然而，SOX 4的独特功能和下游靶点仍有待充分阐明。在这项研究中，我们最初发现SOX 4在黑色素瘤中的表达升高。SOX 4调节细胞凋亡和细胞周期阻滞，影响葡萄糖消耗和乳酸产生，因此促进黑素瘤细胞增殖。此外，我们发现SOX 4通过在转录水平上调节葡萄糖转运蛋白1、己糖激酶2和乳酸脱氢酶A的表达来重新连接葡萄糖代谢。从机制上讲，SOX 4敲低减少了啮齿动物T细胞淋巴瘤和mTORC 1中急性转化逆转录病毒AKT8的激活，导致恶性表型减弱。我们还确定了p70核糖体S6激酶和真核起始因子4E结合蛋白1作为参与黑色素瘤细胞中mTORC 1调控的关键底物。总之，我们的研究证明了SOX 4通过啮齿动物T细胞淋巴瘤信号通路中的急性转化逆转录病毒AKT8在黑色素瘤糖酵解代谢中的重要作用，并强调了其作为黑色素瘤管理中的治疗靶点的潜力。
The sex-determining region Y-related high-mobility group box transcription factor 4 (SOX4) plays a fundamental role during embryogenesis and controls cell fate and differentiation. Recently, increased SOX4 expression has been reported in various cancer types, contributing to the progression and survival of cancer cells. However, the distinct functions and downstream targets of SOX4 remain to be fully elucidated. In this study, we initially found elevated SOX4 expression in melanoma. SOX4 regulates apoptosis and cell cycle arrest, affects glucose consumption and lactate production, and consequently, promotes melanoma cell proliferation. Moreover, we found that SOX4 rewires glucose metabolism by regulating the expression of glucose transporter type 1, hexokinase 2, and lactate dehydrogenase A at the transcriptional level. Mechanistically, SOX4 knockdown reduced activation of acutely transforming retrovirus AKT8 in rodent T-cell lymphoma and mTORC1, leading to an attenuated malignant phenotype. We also identified p70 ribosomal S6 kinase and eukaryotic initiation factor 4E-binding protein 1 as key substrates involved in the regulation of mTORC1 in melanoma cells. In conclusion, our study demonstrates the essential role of SOX4 in melanoma glycolytic metabolism through the acutely transforming retrovirus AKT8 in rodent T-cell lymphoma signaling pathway and highlights its potential as a therapeutic target in melanoma management.