MLK4通过creb介导的磷酸烯醇丙酮酸羧激酶激活促进肺腺癌中的葡萄糖代谢,并受KLF5调控。

IF 5.9 2区 医学 Q1 ONCOLOGY
Alvin Ho-Kwan Cheung, Kit-Yee Wong, Xiaoli Liu, Fenfen Ji, Chris Ho-Lam Hui, Yihan Zhang, Johnny Sheung-Him Kwan, Bonan Chen, Yujuan Dong, Raymond Wai-Ming Lung, Jun Yu, Kwok Wai Lo, Chi Chun Wong, Wei Kang, Ka-Fai To
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引用次数: 0

摘要

MLK4是丝裂原活化蛋白激酶激酶(MAP3K)家族的一员,与癌症进展有关。然而,其在肺腺癌中的作用尚未明确。在这里,我们发现MLK4在肺腺癌的一个重要亚群中过表达,与较差的预后相关,并在体外和体内发挥致癌功能。临床数据集的生物信息学分析确定磷酸烯醇丙酮酸羧激酶1 (PCK1)是MLK4的新靶点。我们证实MLK4通过磷酸化转录因子CREB在转录水平上调控PCK1的表达,从而介导PCK1的表达。我们进一步证明PCK1是肺腺癌的致癌因子。鉴于PCK1在调节细胞代谢中的重要性,我们接下来破译了MLK4的代谢作用。代谢和质谱分析表明,MLK4敲低导致糖酵解显著减少,糖酵解途径代谢物(包括磷酸烯醇丙酮酸酯和乳酸酯)水平降低。最后,通过对MLK4的启动子分析,揭示了转录因子KLF5的一个结合位点,进而正调控MLK4在肺腺癌中的表达。总之,我们发现了KLF5-MLK4-PCK1信号通路参与肺肿瘤发生,并在MAP3K信号通路与肿瘤代谢之间建立了不寻常的联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5.

MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5.

MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5.

MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5.

MLK4, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, has been implicated in cancer progression. However, its role in lung adenocarcinoma has not been characterized. Here, we showed that MLK4 was overexpressed in a significant subset of lung adenocarcinoma, associated with a worse prognosis, and exerted an oncogenic function in vitro and in vivo. Bioinformatics analyses of clinical datasets identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a novel target of MLK4. We validated that MLK4 regulated PCK1 expression at transcriptional level, by phosphorylating the transcription factor CREB, which in turn mediated PCK1 expression. We further demonstrated that PCK1 is an oncogenic factor in lung adenocarcinoma. Given the importance of PCK1 in the regulation of cellular metabolism, we next deciphered the metabolic effects of MLK4. Metabolic and mass spectrometry analyses showed that MLK4 knockdown led to significant reduction of glycolysis and decreased levels of glycolytic pathway metabolites including phosphoenolpyruvate and lactate. Finally, the promoter analysis of MLK4 unravelled a binding site of transcription factor KLF5, which in turn, positively regulated MLK4 expression in lung adenocarcinoma. In summary, we have revealed a KLF5-MLK4-PCK1 signalling pathway involved in lung tumorigenesis and established an unusual link between MAP3K signalling and cancer metabolism.

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来源期刊
Oncogenesis
Oncogenesis ONCOLOGY-
CiteScore
11.90
自引率
0.00%
发文量
70
审稿时长
26 weeks
期刊介绍: Oncogenesis is a peer-reviewed open access online journal that publishes full-length papers, reviews, and short communications exploring the molecular basis of cancer and related phenomena. It seeks to promote diverse and integrated areas of molecular biology, cell biology, oncology, and genetics.
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