Deregulation of DUSP activity in EGFR-mutant lung cancer cell lines contributes to sustained ERK1/2 signaling

Britson, Joel S.; Barton, Frederick D.; Balko, Justin M.; Black, Esther P.

doi:10.1016/j.bbrc.2009.10.061

Cited by 23 publications

(19 citation statements)

References 25 publications

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“…[49]. In addition, deregulation of DUSP4 activity contributes to sustaining ERK signaling, resulting in oncogenic transformation in lung cancer cells [50]. In this study, we reveal that inhibition of G9a attenuates cell proliferation through a DUSP4-mediated pathway, consistent with the above literature supporting that DUSP4 represents a tumor suppressor.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma

Hua

Lin

et al. 2014

Mol Cancer

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BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Emerging evidence indicates that alteration of epigenetics might be a key event in HNSCC progression. Abnormal expression of histone methyltransferase G9a, which contributes to transcriptional repression of tumor suppressors, has been implicated in promoting cancerous malignancies. However, its role in HNSCC has not been previously characterized. In this study, we elucidate the function of G9a and its downstream mechanism in HNSCC.MethodsWe investigated the clinical relevance of G9a in HNSCC using immunohistochemistry (IHC) staining. In vitro cell proliferation and tumorigenesis ability of G9a-manipulated HNSCC cells were examined with MTT assays, clonogenic assays, and soft agar assays. We examined different routes of cell death in HNSCC cells induced by G9a-depletion or enzymatic inhibition by immunoblot, flow cytometry, fluorescent and transmission electron microscopy analysis. Specific targets of G9a were identified by affymetrix microarray and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Lastly, functions of G9a in vivo were confirmed with a xenograft tumor model.ResultsG9a expression is positively correlated to proliferation marker Ki-67 and to poor prognosis in HNSCC patients. Genetic or pharmacological inhibition of G9a reduced cell proliferation without inducing necrosis or apoptosis. Instead, autophagic cell death was the major consequence, and our investigation of mechanisms suggested it is mediated via the dual specificity phosphatase-4 (DUSP4) dependent ERK inactivation pathway. An orthotopic tumor model further confirmed the growth inhibiting effect and induction of autophagy that followed suppression of G9a.ConclusionsIn this study, we provide evidence that G9a confers the survival advantage of HNSCC. Genetic or pharmacological inhibition of G9a induces autophagic cell death; this finding provides a basis for new therapeutic targets for treating HNSCC.

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Section: Discussionsupporting

confidence: 89%

Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma

Hua

Lin

et al. 2014

Mol Cancer

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“…However, in some settings these pathways may cooperate. Consistent with this concept, DUSP4 has been implicated as a growth suppressor in EGFR -mutant lung adenocarcinoma (49) and as a positive activator of ERK in EGFR -mutant lung cancer cell lines (50). A unifying model for EZH2-mediated malignant transformation based on these findings could be the remodeling of chromatin architecture toward a de-differentiated cell state that facilitates proliferative transformation by additional genetic drivers.…”

Section: Discussionmentioning

confidence: 75%

Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer

et al. 2016

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As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically-engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways leading to epigenetic transformation independent from canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a novel and potent EZH2 inhibitor JQEZ5 that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer.

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“…The mechanisms underlying inappropriate signal transmission along the Ras/Raf/MEK/ERK cascade in lung carcinomas are particularly attributed to EGFR overexpression and the presence of Ras mutations, as well as ectopic activation of B-Raf protein (Halilovic et al, 2010;Bansal et al, 1997). Besides, the elevated expression of HSP90 (heat shock protein 90) and loss of enzymatic function of specific mitogen activated protein kinase (MAPK) phosphatases, such as DUSPs (dual-specificity phosphatases), have also been shown to contribute to sustained induction of ERK1/2 activity by controlling the activity and localization of these kinases (Britson et al, 2009). The observations that inhibition of Ras/Raf/ MEK/ERK signaling reduced cell proliferation and/or the migratory phenotype of malignant cells indicate its components as potential targets for cancer treatment (Brognard and Dennis, 2002;Stepulak et al, 2007;Sławi nska-Brych et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…It has been well established that deregulation of the extracellular-signal-regulated kinase (ERK1/2) pathway is a common feature of a variety of human malignancies (Britson et al, 2009). The Ras/Raf/MEK/ERK1/2 signaling cascade has been shown to be a crucial factor involved in cancer cell proliferation and to be responsible for the occurrence of drug resistance in human neoplasias (McCubrey et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Xanthohumol inhibits the extracellular signal regulated kinase (ERK) signalling pathway and suppresses cell growth of lung adenocarcinoma cells

et al. 2016

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Deregulation of DUSP activity in EGFR-mutant lung cancer cell lines contributes to sustained ERK1/2 signaling

Cited by 23 publications

References 25 publications

Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma

Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma

Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer

Xanthohumol inhibits the extracellular signal regulated kinase (ERK) signalling pathway and suppresses cell growth of lung adenocarcinoma cells

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