title: DNA damage induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion.
abstract: DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (NFATc1). However, the upstream regulation of DDIAS expression by growth factors has not been studied. Here, we demonstrate that DDIAS expression is induced by extracellular signal-regulated kinase 5 (ERK5) and myocyte enhancer factor 2B (MEF2B) in response to epidermal growth factor (EGF) and that it positively regulates β-catenin signaling in HeLa cells. The genetic or pharmacological inhibition of ERK5 suppressed DDIAS induction following EGF exposure and the overexpression of constitutively active MEK5 (CA-MEK5) enhanced DDIAS expression. In chromatin immunoprecipitation assays, MEF2B, a downstream target of ERK5, exhibited sequence-specific binding to a MEF2 binding site in the DDIAS promoter following treatment with EGF. The overexpression of MEF2B increased the EGF-mediated induction of DDIAS expression, whereas the knockdown of MEF2B impaired this effect. Furthermore, DDIAS promoted invasion by increasing β-catenin expression at the post-translational level in response to EGF, suggesting that DDIAS plays a crucial role in the metastasis of cancer cells by regulating β-catenin expression. It is unlikely that MEF2B and NFATc1 cooperatively regulate DDIAS transcription in response to EGF. Collectively, EGF activates the ERK5/MEF2 pathway, which in turn induces DDIAS expression to promote cancer cell invasion by activating β-catenin target genes.
authors.affiliation: Genomic Personalized Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Im
authors.affiliation: Genomic Personalized Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, University of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Yoon
authors.affiliation: Genomic Personalized Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Bo-Kyung
authors.initials: BK
authors.lastname: Kim
authors.affiliation: Metabolic Regulation Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Hyun Seung
authors.initials: HS
authors.lastname: Ban
authors.affiliation: Genomic Personalized Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, University of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.affiliation: Metabolic Regulation Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.affiliation: ST Pharm. Co., LTD, Sihwa Industrial Complex 1, Kyunggido, 429-848, Republic of Korea.
authors.forename: Kyeong Eun
authors.initials: KE
authors.lastname: Jung
authors.affiliation: Genomic Personalized Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, University of Science and Technology, Daejeon 305-701, Republic of Korea. Electronic address: misun@kribb.re.kr.
authors.forename: Misun
authors.initials: M
authors.lastname: Won
mesh_terms: D017209:Apoptosis; D004249:DNA Damage; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D064326:MEF2 Transcription Factors / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D064326:MEF2 Transcription Factors; C578038:MEF2B protein, human; D004815:Epidermal Growth Factor; D048054:Mitogen-Activated Protein Kinase 7
keywords: DDIAS; EGF; ERK5; Invasion; MEF2B; β-catenin