title: Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells.
abstract: Mitogen-activated protein kinase (MAPK) pathway signaling plays an important role in the majority of non-small-cell lung cancers (NSCLCs). In a prior microarray analysis of epidermal growth factor receptor (EGFR) inhibition in NSCLC cell lines, we noted that several dual specificity phosphatases (DUSPs) were among the most highly and immediately regulated genes. DUSPs act as natural terminators of MAPK signal transduction and therefore, we hypothesized a tumor suppressive role via feedback mechanisms. In the current study, we focus on the assessment of DUSP6, a cytoplasmic DUSP with high specificity for extracellular signal-regulated kinase (ERK). We demonstrate that DUSP6 expression tracks in tandem with ERK inhibition and that regulation of DUSP6 is mediated at the promoter level by ETS1, a well-known nuclear target of activated ERK. Small interfering RNA knockdown in DUSP6-high H441 lung cancer cells significantly increased ERK activation and cellular proliferation, whereas plasmid-driven overexpression in DUSP6-low H1975 lung cancer cells significantly reduced ERK activation and cellular proliferation and promoted apoptosis. Also, DUSP6 overexpression synergized with EGFR inhibitor treatment in EGFR-mutant HCC827 cells. Our results indicate that DUSP6 expression is regulated by ERK signaling and that DUSP6 exerts antitumor effects via negative feedback regulation, pointing to an important feedback loop in NSCLC. Further studies assessing the tumor suppressive role of DUSP6 and strategies aimed at modulation of its activity are warranted.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals-Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Alain C
authors.initials: AC
authors.lastname: Borczuk
authors.forename: Rom S
authors.initials: RS
authors.lastname: Leidner
authors.forename: Thomas
authors.initials: T
authors.lastname: Laframboise
authors.forename: Alan D
authors.initials: AD
authors.lastname: Levine
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D054642:Dual Specificity Phosphatase 6 / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D025461:Feedback, Physiological; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D050784:Proto-Oncogene Protein c-ets-1 / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6