[Show abstract][Hide abstract] ABSTRACT: Hedgehog (Hh) signaling and the pyruvate kinase isoenzyme M2 (PKM2 or M2-PK) are often involved in tumorigenesis and growth. Aberrant activation of Hh signaling is found in a variety of malignancies. In tumor cells, PKM2 determines whether glucose is used for the synthesis of cellular building blocks or the production of lactate for energy regeneration; it associated with the Warburg effect. Gli1 is a downstream molecule of the Hh signaling pathway; however, the association between Hh signaling and PKM2 is not well understood. In the present study, it was identified that PKM2 and Gli1 expression levels were significantly elevated in hepatocellular carcinoma (HCC) compared with para-carcinoma. In vitro study revealed that overexpression of PKM2 in HepG2 cells upregulated the transcription of Gli1, while the ablation of PKM2 by shRNA caused the downregulation of Gli1 gene expression. Gli1 transcription could be rescued by PKM2. Overall, these findings suggest that PKM2 is a regulator of Gli1 gene expression in HCC, and may contribute to tumorigenesis through Gli1.
[Show abstract][Hide abstract] ABSTRACT: The aberrant activation of the Hedgehog (Hh) signaling pathway has been implicated in a variety of malignancies, including hepatocellular carcinoma (HCC). The mammalian 5' adenosine monophosphate-activated protein kinase (AMPK) plays a crucial role in cellular energy homeostasis. However, the interaction between the Hh and AMPK signaling pathways has not been investigated to date. In the present study, to the best of our knowlege, we report for the first time the negative regulation of glioma-associated oncogene 1 (Gli1), an important downstream effector of Hh, by the AMPK signal transduction pathway. Immunoprecipitation and GST-pull down assay showed a direct interaction between AMPK and Gli1. The overexpression of AMPK induced the downregulation of Gli1 expression, while the knockdown of AMPK upregulated Gli1 expression in a relatively short period of time (24 h or less). Our data suggest that AMPK may function as an upstream molecule that regulates Gli1 expression. Therefore, AMPK may play a role in the Hh signaling pathway, through which it regulates tumorigenesis.
International Journal of Molecular Medicine 07/2014; · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Histone H2B O-GlcNAcylation is an important post-translational modification of chromatin during gene transcription. However, how this epigenetic modification is regulated remains unclear. Here we found that the energy-sensing adenosine-monophosphate-activated protein kinase (AMPK) could suppress histone H2B O-GlcNAcylation. AMPK directly phosphorylates O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT). Although this phosphorylation does not regulate the enzymatic activity of OGT, it inhibits OGT-chromatin association, histone O-GlcNAcylation and gene transcription. Conversely, OGT also O-GlcNAcylates AMPK and positively regulates AMPK activity, creating a feedback loop. Taken together, these results reveal a crosstalk between the LKB1-AMPK and the hexosamine biosynthesis (HBP)-OGT pathways, which coordinate together for the sensing of nutrient state and regulation of gene transcription.
Nucleic Acids Research 04/2014; 42(9). · 8.81 Impact Factor
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[Show abstract][Hide abstract] ABSTRACT: The Hedgehog (Hh) pathway is an evolutionarily conserved signaling mechanism that controls many aspects of cell differentiation and the development of tissues and organs during embryogenesis. Early investigations have focused on the effects of Hh activity on the development of organs including skin, gut, the nervous system and bone. However, in addition to normal developmental processes, these investigations also found that Hh signaling is involved in aberrant proliferation and malignant transformation. Consequently, the role of Hh in cancer pathology, and its modulation by environmental factors is the subject of many investigations. Numerous environmental toxins, alcohol, and hepatitis viruses can cause hepatocellular carcinoma (HCC), which is the most common form of liver cancer. Significant hyperactivation of Hh signaling has been observed in liver injury and cirrhosis which often leads to the development of HCC lesions. Moreover, Hh activity plays an important role in the progression of HCC. Here, we review findings relevant to our understanding of the role of Hh signaling in HCC pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to analyze the mRNA and protein expression of glioma-associated oncogene 1 (Gli1) in hepatocellular carcinoma (HCC) and its correlation with sonic hedgehog (Shh), one of the ligands of hedgehog (Hh) signaling, and two epithelial-mesenchymal transition (EMT) markers, E-cadherin and S100a4. We also investigated the potential crosstalk between Hh signaling and EMT in HCC. Paired HCC and normal tumor-adjacent tissues were freshly collected from 30 primary HCC patients. Gli1 expression at both the mRNA and protein level was examined by reverse transcription-polymerase chain reaction and immunohistochemistry. The protein expression of Shh, E-cadherin and S100a4 was evaluated by immunohistochemistry to identify correlations with Gli1. The mRNA and protein expression of Gli1 was significantly up-regulated in the HCC tumor tissues compared to the normal tumor-adjacent tissues (P<0.01, respectively). Gli1 protein expression in HCC was closely correlated with liver cirrhosis (r=0.460, P=0.011<0.05), intrahepatic metastases (r=0.399, P=0.029<0.05), portal vein invasion (r=0.367, P=0.046<0.05), high Edmonson-Steiner classification (r=0.391, P=0.032<0.05) and advanced TNM stage (r=0.416, P=0.022<0.05). In HCC tissues, Gli1 protein expression was positively correlated with Shh (r=0.584, P=0.001<0.05) and S100a4 (r=0.49, P=0.006<0.05), and negatively correlated with E-cadherin (r=-0.439, P=0.015<0.05). Gli1 was found to be up-regulated in HCC tissues and closely correlated with clinicopathological characteristics, indicating the enhanced metastatic potential of HCC. Furthermore, the increased expression of Gli1 in HCC cells may be attributed to Shh produced aberrantly by the cells themselves. Finally, Gli1 may play an important role in HCC invasion and metastasis by inducing EMT.
Molecular Medicine Reports 3(6):965-70. · 1.48 Impact Factor