title: EZH2 is regulated by ERK/AKT and targets integrin alpha2 gene to control Epithelial-Mesenchymal Transition and anoikis in colon cancer cells.
abstract: Epithelial-Mesenchymal Transition is a good example of cell plasticity. In tumorigenesis, this process has been associated with metastasis. Overexpression of EZH2 has been detected in most malignant human tumors, including colorectal carcinomas. Herein, we provide evidence supporting the idea that oncogenic Epithelial-Mesenchymal Transition in colon cancer cell models is partially controlled by epigenetic factors such as the transcription regulator EZH2. Evaluation of EZH2 mRNA and protein levels revealed overexpression in cell lines with metastatic traits. Analysis of EZH2 mRNA expression was expanded in clinical samples of colon cancer, and high level of EZH2 correlates with appearance of metastasis. Furthermore, inhibition of ERK and AKT pathways in metastatic colon cancer cell lines attenuates EZH2 overexpression. EZH2 promoter analysis illustrates presence of putative AP-1 binding sites and occupancy of transcription factors such as FRA-1 and C-JUN is demonstrated here on EZH2 promoter. Abrogation of EZH2 expression impairs the ability of colon cancer cells to move associated with anoikis in three-dimensional environment. Integrin alpha2 was identified to be a novel EZH2 target by chromatin immunoprecipitation and short hairpin RNA analysis. This study proposes that activation of ERK/AKT pathways and FRA1/C-JUN induce EZH2 overexpression, which results in Integrin alpha2 silencing. Our results show how deregulation of epigenetic factors and mechanisms can affect cancer cell aggressiveness and propose EZH2 as a potential metastasis marker and/or therapeutic target for colorectal cancer treatment.
authors.affiliation: Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, 11635, Greece.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ferraro
authors.forename: Despoina
authors.initials: D
authors.lastname: Mourtzoukou
authors.forename: Vivian
authors.initials: V
authors.lastname: Kosmidou
authors.forename: Spiros
authors.initials: S
authors.lastname: Avlonitis
authors.forename: George
authors.initials: G
authors.lastname: Kontogeorgos
authors.forename: George
authors.initials: G
authors.lastname: Zografos
authors.forename: Alexander
authors.initials: A
authors.lastname: Pintzas
mesh_terms: D023102:Anoikis; D018938:Caco-2 Cells; D002465:Cell Movement; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008207:Lymphatic Metastasis; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D039421:Integrin alpha2; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases