Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is currently the sixth most common cancer worldwide and remains an extremely complex condition with a poor prognosis [1, 2]
In the present study, based on evidence from clinical samples that phosphorylation of Peroxisome proliferator-activating receptor γ (PPARγ) at Ser84 is up-regulated in human liver tumours, we confirmed that phosphorylation of PPARγ was significantly increased in an hepatocellular carcinoma (HCC) mouse model and was increased by Mitogen-activated protein kinase (MEK)/ Extracellular-signalregulated kinases (ERK) kinase
We show for the first time that PPARγ phosphorylation at Ser84/Ser82/Ser84 was up-regulated in mouse (Ser82)( Ser112 in PPARγ2) occurs in the majority of HCC cases investigated and in liver tumours from human samples and a mouse model, whereas blockade of PPARγ phosphorylation by a kinase inhibitor or site-mutation both decrease the aggressiveness and tumourigenicity of hepatoma/hepatocarcinoma cells
Summary
Hepatocellular carcinoma (HCC) is currently the sixth most common cancer worldwide and remains an extremely complex condition with a poor prognosis [1, 2]. The alterations to transcription factor function confer the specific advantages necessary for hepatocyte transformation and thereafter the fate of hepatocarcinoma cells [10, 11]. Numerous studies have proven that PPARγ is involved in many www.impactjournals.com/oncotarget important biological processes, including cell terminal differentiation, survival and apoptosis, and thereby plays an essential role in regulating adipogenesis, inflammation, tumourigenesis and metastasis etc.[12]. There have been encouraging reports revealing that PPARγ activation prevents cancer in tissues such as colon, breast, prostate, lung and liver [14], justifying that PPARγ agonists may be useful in hepatocellular carcinoma therapy [15]. The use of PPARγ agonists (pioglitazone and rosiglitazone) is associated with decreased liver cancer incidence [16]. All of the evidence above stimulated studies on the role of PPARγ in HCC and the possibility of targeting it
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