title: Identification of HDAC4 as a target of γ-catenin that regulates the oncogenic K-Ras-mediated malignant phenotype of Rat2 cells.
abstract: The mechanisms by which activated Ras accelerates malignant transformation of normal cells are not fully understood. Here, we characterized the role and molecular mechanism of γ-catenin in regulating the malignant phenotype of Rat2 cells induced by codon 12-mutant K-Ras (K-Ras12V). Suppression of γ-catenin signaling by K-Ras12V was an early event and played a crucial role in promoting the acquisition of a highly metastatic phenotype of Rat2 cells. Notably, the gene encoding histone deacetylase 4 (HDAC4) was identified as a target of γ-catenin during this process. The transcription factor, lymphoid enhancer-binding factor-1 (Lef1), was involved in the modulation of HDAC4 transcription, and disruption of this pathway was a key event in promoting the invasion and migration of K-Ras12V-transduced Rat2 cells. Thus, our findings extend the range of targets for the development of new drugs for the therapy of oncogenic K-Ras-driven cancer.
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yim
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Baek
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Lee
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Hong Shik
authors.initials: HS
authors.lastname: Yun
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Hong
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D010641:Phenotype; D025941:Protein Interaction Mapping; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495268:Ctnnb1 protein, rat; C497575:Lef1 protein, rat; D051821:Lymphoid Enhancer-Binding Factor 1; D034741:RNA, Small Interfering; D051176:beta Catenin; D051185:gamma Catenin; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases
keywords: HDAC4; Lef1; Oncogenic K-Ras; Rat2 fibroblast cells; γ-Catenin