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2.
Mol Cancer ; 13: 172, 2014 Jul 15.
Article in English | MEDLINE | ID: mdl-25027955

ABSTRACT

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Emerging evidence indicates that alteration of epigenetics might be a key event in HNSCC progression. Abnormal expression of histone methyltransferase G9a, which contributes to transcriptional repression of tumor suppressors, has been implicated in promoting cancerous malignancies. However, its role in HNSCC has not been previously characterized. In this study, we elucidate the function of G9a and its downstream mechanism in HNSCC. METHODS: We investigated the clinical relevance of G9a in HNSCC using immunohistochemistry (IHC) staining. In vitro cell proliferation and tumorigenesis ability of G9a-manipulated HNSCC cells were examined with MTT assays, clonogenic assays, and soft agar assays. We examined different routes of cell death in HNSCC cells induced by G9a-depletion or enzymatic inhibition by immunoblot, flow cytometry, fluorescent and transmission electron microscopy analysis. Specific targets of G9a were identified by affymetrix microarray and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Lastly, functions of G9a in vivo were confirmed with a xenograft tumor model. RESULTS: G9a expression is positively correlated to proliferation marker Ki-67 and to poor prognosis in HNSCC patients. Genetic or pharmacological inhibition of G9a reduced cell proliferation without inducing necrosis or apoptosis. Instead, autophagic cell death was the major consequence, and our investigation of mechanisms suggested it is mediated via the dual specificity phosphatase-4 (DUSP4) dependent ERK inactivation pathway. An orthotopic tumor model further confirmed the growth inhibiting effect and induction of autophagy that followed suppression of G9a. CONCLUSIONS: In this study, we provide evidence that G9a confers the survival advantage of HNSCC. Genetic or pharmacological inhibition of G9a induces autophagic cell death; this finding provides a basis for new therapeutic targets for treating HNSCC.


Subject(s)
Carcinoma, Squamous Cell/genetics , Dual-Specificity Phosphatases/genetics , Head and Neck Neoplasms/genetics , Histocompatibility Antigens/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Mitogen-Activated Protein Kinase Phosphatases/genetics , Animals , Autophagy/genetics , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/genetics , Dual-Specificity Phosphatases/metabolism , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/pathology , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Humans , MAP Kinase Signaling System/genetics , Mice , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Xenograft Model Antitumor Assays
3.
Toxicol Appl Pharmacol ; 237(3): 281-7, 2009 Jun 15.
Article in English | MEDLINE | ID: mdl-19361540

ABSTRACT

Mycotoxin citrinin (CTN) is commonly found in foods and feeds that are contaminated/inoculated with Penicillium, Aspergillus and Monascus species. The exposure of human embryonic kidney (HEK293) and HeLa cells to CTN resulted in a dose-dependent increase in the phosphorylation of two major mitogen-activated protein kinases (MAPKs), ERK1/2 and JNK. In HEK293 cultures, the administering of CTN increased both the mRNA and protein levels of egr-1, c-fos and c-jun genes; additionally, the ERK1/2 pathway contributed to the upregulation of Egr-1 and c-Fos protein expression. CTN treatment also induced the transcription activity of Egr-1 and AP-1 proteins, as evidenced by luciferase reporter assays. Bioinformatic analyses indicated two genes Gadd45 beta and MMP3 have Egr-1 and AP-1 response elements in their promoters, respectively. Furthermore, co-exposure of HEK293 cells to CTN and MAPK pathway inhibitors demonstrated that CTN increased the levels of Gadd45 beta mRNA through ERK1/2 signaling pathway and up-regulated the MMP3 transcripts majorly via JNK pathway. Finally, CTN-triggered caspase 3 activity was significantly reduced in the presence of MAPK inhibitors. Our results suggest that CTN positively regulates ERK1/2 and JNK pathways as well as their downstream effectors in human cells; activated MAPK pathways are also involved in CTN-induced apoptosis.


Subject(s)
Citrinin/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinase 3/metabolism , Cell Line , Enzyme Activation/drug effects , Enzyme Activation/physiology , HeLa Cells , Humans , Immediate-Early Proteins/biosynthesis , Immediate-Early Proteins/genetics , JNK Mitogen-Activated Protein Kinases/physiology , Mitogen-Activated Protein Kinase 3/physiology , Transcriptional Activation/drug effects
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