EGR1 decreases the malignancy of human non-small cell lung carcinoma by regulating KRT18 expression

Zhang, Huihua; Chen, Xiaojia; Wang, Jia-Kang; Guang, Wenhua; Han, Wei; Zhang, Hang; Tan, Xuan Ni; Gu, Yong

doi:10.1038/srep05416

Cited by 65 publications

(62 citation statements)

References 34 publications

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“…Although Egr1 DNA-binding sites are absent from our SerpinB2 promoter-reporter constructs, knockdown of Egr1 inhibits AP1-dependent SerpinB2 transcriptional activity. This suggests an indirect effect of Egr1 on SerpinB2, possibly via the regulation of AP1 itself (26). DUSP5 was recently identified as an Egr1 target gene in TPA-treated leukemia (THP-1) cells (27), which is compatible with our proposal that by regulating ERK-dependent Egr1 levels, DUSP5 acts as part of a negative feedback loop to regulate its own expression.…”

Section: Discussionsupporting

confidence: 76%

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas ^Q61L )-driven SerpinB2 expression

Rushworth

Kidger

Delavaine

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Ectopic expression of dual-specificity phosphatase 5 (DUSP5), an inducible mitogen-activated protein (MAP) kinase phosphatase, specifically inactivates and anchors extracellular signal-regulated kinase (ERK)1/2 in the nucleus. However, the role of endogenous DUSP5 in regulating the outcome of Ras/ERK kinase signaling under normal and pathological conditions is unknown. Here we report that mice lacking DUSP5 show a greatly increased sensitivity to mutant Harvey-Ras (HRas Q61L )-driven papilloma formation in the 7,12-Dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) model of skin carcinogenesis. Furthermore, mouse embryo fibroblasts (MEFs) from DUSP5 −/− mice show increased levels of nuclear phospho-ERK immediately after TPA stimulation and fail to accumulate total ERK in the nucleus compared with DUSP5 +/+ cells. Surprisingly, a microarray analysis reveals that only a small number of Ras/ERK-dependent TPA-responsive transcripts are up-regulated on deletion of DUSP5 in MEFs and mouse skin. The most up-regulated gene on DUSP5 loss encodes SerpinB2, an inhibitor of extracellular urokinase plasminogen activator and deletion of DUSP5 acts synergistically with mutant HRas Q61L and TPA to activate ERK-dependent SerpinB2 expression at the transcriptional level. SerpinB2 has previously been implicated as a mediator of DMBA/TPA-induced skin carcinogenesis. By analyzing DUSP5−/− double knockout mice, we demonstrate that deletion of SerpinB2 abrogates the increased sensitivity to papilloma formation seen on DUSP5 deletion. We conclude that DUSP5 performs a key nonredundant role in regulating nuclear ERK activation, localization, and gene expression. Furthermore, our results suggest an in vivo role for DUSP5 as a tumor suppressor by modulating the oncogenic potential of activated Ras in the epidermis.is one of four mammalian inducible, nuclear mitogen-activated protein kinase (MAPK) phosphatases (MKPs) (1). However, DUSP5 is unique within this group in targeting only the classical extracellular signal-regulated kinases 1 and 2 (referred to hereafter as ERK) (2). This, coupled with the finding that ERK activation is required for inducible DUSP5 expression, indicates that it acts as a negative feedback regulator of nuclear Ras/ERK signaling (3). DUSP5 overexpression also leads to nuclear accumulation of endogenous ERK (2), suggesting that DUSP5 may also act as a nuclear anchor, thus regulating both the spatial organization and activity of the pathway (4).Ras/ERK signaling is frequently deregulated in human cancers due to activating mutations in pathway components such as growth factor receptors, Ras GTPases, and the MAPK kinase kinase, BRaf (5). BRaf is mutated in 40-60% of malignant melanomas as well as in thyroid, colorectal, and lung tumors, underscoring the importance of this pathway and making it a focus of anticancer drug development (6). Whereas mechanisms of Ras/MAPK pathway activation in cancer are understood, little is known about how negative feedback controls influence tumorigenesis (7). Stud...

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Section: Discussionsupporting

confidence: 76%

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas ^Q61L )-driven SerpinB2 expression

Rushworth

Kidger

Delavaine

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…EGR1 and RHOB are newly identified tumor suppressors, and their loss is frequently observed during lung cancer development and progression. 29,30 Therefore, we assumed that DUXAP8 contributes to NSCLC by repressing EGR1 and RHOB expression. Accordingly, we used western blot analysis to examine their protein levels in H1299 and H1975 cells transfected with DUXAP8 or control siRNA.…”

Section: Egr1 and Rhob Are Key Downstream Targets Of Duxap8 In Nsclc mentioning

confidence: 99%

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

et al. 2017

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Recently, the non-protein-coding functional elements in the human genome have been identified as key regulators in postgenomic biology, and a large number of pseudogenes as well as long non-coding RNAs (lncRNAs) have been found to be transcribed in multiple human cancers. However, only a small proportion of these pseudogenes has been functionally characterized. In this study, we screened for pseudogenes associated with human non-small-cell lung cancer (NSCLC) by comparative analysis of several independent datasets from the GEO. We identified a transcribed pseudogene named DUXAP8 that is upregulated in tumor tissues. Patients with higher DUXAP8 expression exhibited shorter survival, suggesting DUXAP8 as a new candidate prognostic marker for NSCLC patients. Knockdown of DUXAP8 impairs cell growth, migration, and invasion, and induces apoptosis both in vitro and in vivo. Mechanistically, DUXAP8 represses the tumor suppressors EGR1 and RHOB by recruiting histone demethylase LSD1 and histone methyltransferase EZH2, thereby promoting cell proliferation, migration, and invasion. These findings indicate that the pseudogene DUXAP8 may act as an oncogene in NSCLC by silencing EGR1 and RHOB transcription by binding with EZH2 and LSD1, which may offer a novel therapeutic target for this disease.

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“…EGR1 encodes an ERK-induced transcriptional regulator whose target genes have various roles in differentiation and mitogenesis. EGR1 was found to arrest cell mobility, inhibit migration and induce apoptosis in human non-small-cell lung carcinoma cells [36]. It has previously been observed to be downregulated in HCC [20].…”

Section: Discussionmentioning

confidence: 99%

Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium

Cartularo

Laulicht

Sun

et al. 2015

Toxicology and Applied Pharmacology

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Cadmium (Cd) is a toxic and carcinogenic metal naturally occurring in the earth’s crust. A common route of human exposure is via diet and cadmium accumulates in the liver. The effects of Cd exposure on gene expression in human hepatocellular carcinoma (HepG2) cells were examined in this study. HepG2 cells were acutely-treated with 0.1, 0.5, or 1.0 μM Cd for 24 hours; or chronically-treated with 0.01, 0.05, or 0.1 μM Cd for three weeks and gene expression analysis was performed using Affymetrix GeneChip® Human Gene 1.0 ST Arrays. Acute and chronic exposures significantly altered the expression of 333 and 181 genes, respectively. The genes most upregulated by acute exposure included several metallothioneins. Downregulated genes included the monooxygenase CYP3A7, involved in drug and lipid metabolism. In contrast, CYP3A7 was upregulated by chronic Cd exposure, as was DNAJB9, an anti-apoptotic J protein. Genes downregulated following chronic exposure included the transcriptional regulator early growth response protein 1. Ingenuity Pathway Analysis revealed that the top networks altered by acute exposure were lipid metabolism, small molecule biosynthesis, and cell morphology, organization, and development; while top networks altered by chronic exposure were organ morphology, cell cycle, cell signaling, and renal and urological diseases/cancer. Many of the dysregulated genes play important roles in cellular growth, proliferation, and apoptosis, and may be involved in carcinogenesis. In addition to gene expression changes, HepG2 cells treated with cadmium for 24 hours indicated a reduction in global levels of histone methylation and acetylation that persisted 72 hours post-treatment.

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EGR1 decreases the malignancy of human non-small cell lung carcinoma by regulating KRT18 expression

Cited by 65 publications

References 34 publications

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas ^Q61L )-driven SerpinB2 expression

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas ^Q61L )-driven SerpinB2 expression

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium

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EGR1 decreases the malignancy of human non-small cell lung carcinoma by regulating KRT18 expression

Cited by 65 publications

References 34 publications

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas Q61L )-driven SerpinB2 expression

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas Q61L )-driven SerpinB2 expression

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium

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Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas ^Q61L )-driven SerpinB2 expression

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas ^Q61L )-driven SerpinB2 expression