Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Bonazzi, Vanessa; Irwin, Darryl; Hayward, Nicholas K.

doi:10.1002/gcc.20615

Cited by 70 publications

(56 citation statements)

References 52 publications

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“…We also observed enrichment for miR-129 target sites in down-regulated transcripts in vitro following T24 cell transfection with miR-129 precursor. Among the downregulated miR-129 targets, we found TP53INP1, which has been shown to have a tumor suppressor function in melanoma (45), and BMPR2, which has been reported to be associated with development of colorectal cancer (46). We showed that the down-regulated targets SOX4 and GALNT1 were direct targets for miR-129 in luciferase assays.…”

Section: Discussionmentioning

confidence: 78%

Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Dyrskjøt¹,

Ostenfeld²,

et al. 2009

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microRNAs (miRNA) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Here, we profiled the expression of 290 unique human miRNAs in 11 normal and 106 bladder tumor samples using spotted locked nucleic acid-based oligonucleotide microarrays. We identified several differentially expressed miRNAs between normal urothelium and cancer and between the different disease stages. miR-145 was found to be the most down-regulated in cancer compared with normal, and miR-21 was the most upregulated in cancer. Furthermore, we identified miRNAs that significantly correlated to the presence of concomitant carcinoma in situ. We identified several miRNAs with prognostic potential for predicting disease progression (e.g., miR-129, miR-133b, and miR-518c*). We localized the expression of miR-145, miR-21, and miR-129 to urothelium by in situ hybridization. We then focused on miR-129 that exerted significant growth inhibition and induced cell death upon transfection with a miR-129 precursor in bladder carcinoma cell lines T24 and SW780 cells. Microarray analysis of T24 cells after transfection showed significant miR-129 target downregulation (P = 0.0002) and pathway analysis indicated that targets were involved in cell death processes. By analyzing gene expression data from clinical tumor samples, we identified significant expression changes of target mRNA molecules related to the miRNA expression. Using luciferase assays, we documented a direct link between miR-129 and the two putative targets GALNT1 and SOX4. The findings reported here indicate that several miRNAs are differentially regulated in bladder cancer and may form a basis for clinical development of new biomarkers for bladder cancer. [Cancer Res 2009;69(11):4851-60]

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Section: Discussionmentioning

confidence: 78%

Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Dyrskjøt¹,

Ostenfeld²,

et al. 2009

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“…TIMP3 has been shown to inhibit tumor growth, invasion and angiogenesis, and has previously been established as a hypermethylated and downregulated gene in breast cancer (Lui et al, 2005). TP53INP1, which plays a role in both cell cycle arrest and p53-mediated apoptosis (Weng et al, 2011), has been shown to be decreased in melanoma and its reduced expression was correlated with hypermethylation of a promoter (Bonazzi et al, 2009). Notable cancer-related genes within the TNF-α-dependent apoptosis pathways that were upregulated in the Aza-treated MCF-7 cells included TNFSF10 (2.1-fold increase in both 5 and 10 μM Aza treated cells) and ICAM1 (2.3-fold increase in both 5 and 10 μM Aza treated cells).…”

Section: Aza Induced Genome-wide Demethylation In Mcf-7 Cellsmentioning

confidence: 99%

Expression Profiling after Induction of Demethylation in MCF-7 Breast Cancer Cells Identifies Involvement of TNF-α Mediated Cancer Pathways

Kim

Kang

Kim

et al. 2012

Molecules and Cells

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“…IL-6, a target of C/EBP␤, is a mediator of the oncogene-induced senescence program triggered by the oncogenic BRAF E600 allele in human fibroblasts (51). The gene for PPP1R3C (protein phosphatase 1 regulatory subunit 3C) is hypermethylated in several cancers and is a candidate tumor suppressor gene (52)(53)(54)(55)(56). CBLB (Cas-Br-M retroviral transforming sequence b), a member of the Cbl family of ubiquitin ligases, promotes mono-ubiquitination of proteins targeted for lysosomal degradation (57).…”

Section: Discussionmentioning

confidence: 99%

JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells

Maslikowski

Wang

et al. 2017

J Virol

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The increase in AP-1 activity is a hallmark of cell transformation by tyrosine kinases. Previously, we reported that blocking AP-1 using the c-Jun dominant negative mutant TAM67 induced senescence, adipogenesis, or apoptosis in v-Srctransformed chicken embryo fibroblasts (CEFs) whereas inhibition of JunD by short hairpin RNA (shRNA) specifically induced apoptosis. To investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEFs expressing either TAM67 or the JunD shRNA. Our study revealed a cluster of 18 probe sets upregulated exclusively in response to AP-1/JunD impairment and v-Src transformation. Four of these probe sets correspond to genes involved in the interferon pathway. One gene in particular, death-associated protein kinase 1 (DAPK1), is a C/EBP␤-regulated mediator of apoptosis in gamma interferon (IFN-␥)-induced cell death. Here, we show that inhibition of DAPK1 abrogates cell death in v-Src-transformed cells expressing the JunD shRNA. Chromatin immunoprecipitation data indicated that C/EBP␤ was recruited to the DAPK1 promoter while the expression of a dominant negative mutant of C/EBP␤ abrogated the induction of DAPK1 in response to the inhibition of AP-1. In contrast, as determined by chromatin immunoprecipitation (ChIP) assays, JunD was not detected on the DAPK1 promoter under any conditions, suggesting that JunD promotes survival by indirectly antagonizing the expression of DAPK1 in v-Src transformed cells.IMPORTANCE Transformation by the v-Src oncoprotein causes extensive changes in gene expression in primary cells such as chicken embryo fibroblasts. These changes, determining the properties of transformed cells, are controlled in part at the transcriptional level. Much attention has been devoted to transcription factors such as AP-1 and NF-B and the control of genes associated with a more aggressive phenotype. In this report, we describe a novel mechanism of action determined by the JunD component of AP-1, a factor enhancing cell survival in v-Src-transformed cells. We show that the loss of JunD results in the aberrant activation of a genetic program leading to cell death. This program requires the activation of the tumor suppressor death-associated protein kinase 1 (DAPK1). Since DAPK1 is phosphorylated and inhibited by v-Src, these results highlight the importance of this kinase and the multiple mechanisms controlled by v-Src to antagonize the tumor suppressor function of DAPK1.KEYWORDS AP-1, C/EBP␤, DAPK1, JunD, transformation, v-Src T he Src nonreceptor tyrosine kinase has served as the prototypical kinase model for signaling in vertebrates. Understanding the fundamental basis for Src signaling has provided insight into both the normal function of kinase signaling in the cell as well as contributing to the understanding of human disease. In particular, high Src activity has been linked to poor prognosis and metastasis in breast and colon cancers (1, 2). Given Src's role in human disease, v...

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Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Cited by 70 publications

References 52 publications

Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro

Expression Profiling after Induction of Demethylation in MCF-7 Breast Cancer Cells Identifies Involvement of TNF-α Mediated Cancer Pathways

JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells

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