Phosphorylation of PPARγ at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4.
Phosphorylation of PPARγ at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4.
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PPARγ Ser84 磷酸化通过靶向 PFKFB4 促进肝细胞癌中的糖酵解和细胞增殖
DOI：
10.18632/oncotarget.12764
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发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Shen P
中科院分区：
文献类型：
--
作者：
Shu Y;Lu Y;Pang X;Zheng W;Huang Y;Li J;Ji J;Zhang C;Shen P
过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activating receptor γ，PPARγ）是一种转录因子，参与细胞终末分化、存活和凋亡等重要生物学过程。然而，在肝细胞癌（HCC）中，调节肿瘤启动子和癌基因表达的PPARγ的作用尚不清楚。在本研究中，基于来自临床样本的证据，即人类肝脏肿瘤中Ser 84处的PPARγ磷酸化上调，我们证实了在HCC小鼠模型中，PPARγ的磷酸化也显著增加，并且通过丝裂原活化蛋白激酶（MEK）/细胞外信号调节激酶（ERK）激酶增加。接下来，我们进行了RNA微阵列分析，我们的数据表明，PPARγ在Ser 84的去磷酸化影响糖酵解相关基因和促增殖基因的表达，这可能促进HCC细胞的增殖。使用染色质免疫沉淀（ChIP）分析，我们证明观察到的PPARγ介导的6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶4（PFKFB 4）表达的诱导直接受其启动子的转录活性调节。此外，通过敲低PFKFB 4，我们阐明了PPARγ磷酸化对HCC中糖酵解和增殖的刺激依赖于PFKFB 4。总之，这些发现扩展了我们对肝脏肿瘤细胞如何通过特定转录因子的翻译后修饰重新编程其糖酵解途径的理解，并为筛选治疗HCC的新靶点奠定了基础。
Peroxisome proliferator-activating receptor γ (PPARγ), a transcription factor, is involved in many important biological processes, including cell terminal differentiation, survival and apoptosis. However, the role of PPARγ, which regulates tumour promoter and oncogene expression, is not well understood in hepatocellular carcinoma (HCC). In the present study, based on evidence from clinical samples that phosphorylation of PPARγ at Ser84 is up-regulated in human liver tumours, we confirmed that phosphorylation of PPARγ was also significantly increased in an HCC mouse model and was increased by Mitogen-activated protein kinase (MEK)/ Extracellular-signal-regulated kinases (ERK) kinase. Next, we performed an RNA microarray analysis, and our data indicated that dephosphorylation of PPARγ at Ser84 affects the expression of glycolysis-related genes and pro-proliferation genes, which supposedly promote proliferation of HCC cells. Using a chromatin immunoprecipitation (ChIP) assay, we demonstrated that the observed PPARγ-mediated induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) expression was directly modulated by the transcriptional activity of its promoter. Furthermore, using knockdown of PFKFB4, we elucidated that the stimulation of PPARγ phosphorylation on glycolysis and proliferation in HCC is dependent on PFKFB4. Together, these findings extend our understanding of how liver tumour cells reprogram their glycolytic pathways by post-translational modification of specific transcription factors and lay a foundation for the screening of new targets for the treatment of HCC.