Loss of keratins 8 and 18 leads to alterations in α6β4-integrin-mediated signalling and decreased neoplastic progression in an oral-tumour-derived cell line

Alam, Hunain; Kundu, Samrat T.; Dalal, Sorab N.; Vaidya, Milind M.

doi:10.1242/jcs.073585

Cited by 55 publications

(91 citation statements)

References 56 publications

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“…αvβ6 integrin was found to be significantly upregulated in certain cancer types including colon (18,26) and ovarian carcinoma (27) and in early stage non-small cell lung cancer (NSCLC) (28). In the present study, β6 integrin expression was upregulated in many breast cancer samples and high expression of β6 integrin was found to be associated with poor prognosis.…”

Section: Discussionsupporting

confidence: 47%

Binding of MMP-9-degraded fibronectin to β6 integrin promotes invasion via the FAK-Src-related Erk1/2 and PI3K/Akt/Smad-1/5/8 pathways in breast cancer

Liu

Zhao

et al. 2015

Oncology Reports

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Abstract. Fibronectin (FN) has been recognized as the key element in promoting cell adhesion, migration and oncogenic transformation. αvβ6 integrin binds with FN in an RGD-dependent manner and is associated with invasion and poor prognosis in many types of cancers. The extracellular matrix (ECM) is commonly degraded and becomes disorganized in cancers. Previous studies have shown that FN can be degraded into fragments by MMP-9 in vitro; MMP-9 expression is upregulated in breast cancer, therefore, the role of degraded FN in breast cancer progression needs to be investigated. In the present study, expression of β6 integrin in breast cancer tissues was analyzed. The data were quite consistent with the hypothesis that β6 integrin expression is an indicator of poor prognosis. Cell surface expression of β6 integrin was correlated with the invasive behavior of the breast cancer cell lines. MMP-9-degraded FN was used to explore its effects on cell invasion and expression of β6 integrin. The results indicated that MMP-9-degraded FN can adjust constituents of the αvβ6 heterodimers at the early phase and significantly elevate amounts of β6 integrin subunits at a later period. To better elucidate the mechanism by which β6 integrin regulates FN-induced cell migration and invasion, we determined the expression and activity of the downstream kinases of β6 integrin, and elucidated that focal adhesion kinase (FAK)-Src interaction promoted the invasion and migration of breast cancer cells after treatment of MMP-9-degraded FN through the Erk1/2 and PI3K/Akt/Smad-1/5/8 pathways.

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Section: Discussionsupporting

confidence: 47%

Binding of MMP-9-degraded fibronectin to β6 integrin promotes invasion via the FAK-Src-related Erk1/2 and PI3K/Akt/Smad-1/5/8 pathways in breast cancer

Liu

Zhao

et al. 2015

Oncology Reports

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“…For the orthotopic mouse xenograft model, mice were sacrificed at the 13th week after injection, and the lungs and lymph nodes were inspected for metastasis, which were confirmed by H&E staining. To further determine the effect of KMD2A knockdown on tumorigenicity of H1792 cells, 2 × 10 6 cells were subcutaneously injected into the dorsal flank of 6-to 8-week-old nude mice as previously described (36). Control or KDM2A-depleted H1792 cells were suspended in RPMI without serum before injection.…”

Section: Methodsmentioning

confidence: 99%

KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling

Wagner¹,

et al. 2013

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Epigenetic dysregulation has emerged as a major contributor to tumorigenesis. Histone methylation is a wellestablished mechanism of epigenetic regulation that is dynamically modulated by histone methyltransferases and demethylases. The pathogenic role of histone methylation modifiers in non-small cell lung cancer (NSCLC), which is the leading cause of cancer deaths worldwide, remains largely unknown. Here, we found that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is frequently overexpressed in NSCLC tumors and cell lines. KDM2A and its catalytic activity were required for in vitro proliferation and invasion of KDM2A-overexpressing NSCLC cells. KDM2A overexpression in NSCLC cells with low KDM2A levels increased cell proliferation and invasiveness. KDM2A knockdown abrogated tumor growth and invasive abilities of NSCLC cells in mouse xenograft models. We identified dual-specificity phosphatase 3 (DUSP3) as a key KDM2A target gene and found that DUSP3 dephosphorylates ERK1/2 in NSCLC cells. KDM2A activated ERK1/2 through epigenetic repression of DUSP3 expression via demethylation of dimethylated H3K36 at the DUSP3 locus. High KDM2A levels correlated with poor prognosis in NSCLC patients. These findings uncover an unexpected role for a histone methylation modifier in activating ERK1/2 in lung tumorigenesis and metastasis, suggesting that KDM2A may be a promising therapeutic target in NSCLC.

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“…KDM2A-depleted cells were generated using shRNA against KDM2A as described previously (21). KDM2A/ HDAC3-depleted cells were generated by treating KDM2A-depleted cells with 50 nM siHDAC3-9 using Lipofectamine RNAiMAX.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

Dhar

Alam

et al. 2014

Journal of Biological Chemistry

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Background: Overexpression of the epigenetic repressor KDM2A promotes lung tumorigenesis. Results: Transcriptional inhibition of HDAC3 expression by KDM2A releases cell cycle and proinvasive genes from HDAC3-mediated repression and positively regulates cell proliferation and invasiveness. Conclusion: KDM2A-mediated repression of HDAC3 is linked to KDM2A-promoted tumorigenicity. Significance: Our findings provide a novel epigenetic insight into how KDM2A promotes lung tumorigenesis and have implications for therapeutic intervention.

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Loss of keratins 8 and 18 leads to alterations in α6β4-integrin-mediated signalling and decreased neoplastic progression in an oral-tumour-derived cell line

Cited by 55 publications

References 56 publications

Binding of MMP-9-degraded fibronectin to β6 integrin promotes invasion via the FAK-Src-related Erk1/2 and PI3K/Akt/Smad-1/5/8 pathways in breast cancer

Binding of MMP-9-degraded fibronectin to β6 integrin promotes invasion via the FAK-Src-related Erk1/2 and PI3K/Akt/Smad-1/5/8 pathways in breast cancer

KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

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