Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells

Zhenfeng Zhang, Susumu Kobayashi, Alain C. Borczuk, Rom S. Leidner, Thomas LaFramboise, Alan D. Levine, Balazs Halmos

Research output: Contribution to journalArticle

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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 signalregulated 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.

Original languageEnglish (US)
Pages (from-to)577-586
Number of pages10
JournalCarcinogenesis
Volume31
Issue number4
DOIs
StatePublished - Jan 22 2010
Externally publishedYes

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Dual Specificity Phosphatase 6
Lung Neoplasms
Phosphotransferases
Dual-Specificity Phosphatases
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Mitogen-Activated Protein Kinases
Cell Proliferation
Microarray Analysis
Small Interfering RNA
Signal Transduction
Neoplasms
Plasmids

ASJC Scopus subject areas

  • Cancer Research

Cite this

Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. / Zhang, Zhenfeng; Kobayashi, Susumu; Borczuk, Alain C.; Leidner, Rom S.; LaFramboise, Thomas; Levine, Alan D.; Halmos, Balazs.

In: Carcinogenesis, Vol. 31, No. 4, 22.01.2010, p. 577-586.

Research output: Contribution to journalArticle

Zhang, Zhenfeng ; Kobayashi, Susumu ; Borczuk, Alain C. ; Leidner, Rom S. ; LaFramboise, Thomas ; Levine, Alan D. ; Halmos, Balazs. / Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. In: Carcinogenesis. 2010 ; Vol. 31, No. 4. pp. 577-586.
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