ETV1 positively regulates transcription of tumor suppressor ARF

Zynda, Evan R.; Jackson, Mark W.; Bhattacharya, Partho; Kandel, Eugene

doi:10.4161/cbt.26883

Cited by 3 publications

(3 citation statements)

References 53 publications

(48 reference statements)

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“…Importantly, we present evidence that ETV1 suppresses motility and migration of melanoma cells and therefore function as a tumor suppressor. To the best of our knowledge, there is only one report, on fibrosarcoma, that suggests an inhibitory role for ETV1, resulting in increased expression of mRNA of p14ARF [ 52 ], a known tumor suppressor which activates p53 [ 53 ]. Worth noting, the majority of melanomas in fact lack ETV1 amplification, representing > 80% of the cases [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

miR-17 regulates melanoma cell motility by inhibiting the translation of ETV1

et al. 2015

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Melanoma is an aggressive malignancy with a high metastatic potential. microRNA-17 (miR-17) is a member of the oncogenic miR-17/92 cluster. Here we study the effect of miR-17 on melanoma cell motility. Over expression of the mature or pri-microRNA form of miR-17 in WM-266-4 and 624mel melanoma lines enhances cell motility, evident in both wound healing and transwell migration assays. TargetScan algorithm predicts the PEA3-subfamily member ETV1 as a direct target of miR-17. Indeed, a 3–4-fold decrease of ETV1 protein levels are observed following miR-17 transfection into the various melanoma lines, with no significant change in ETV1 mRNA expression. Dual luciferase experiments demonstrate direct binding of miR-17 to the 3′-untranslated region of ETV1, confirmed by abolishing point mutations in the putative binding site. These combined results suggest regulation of ETV1 by miR-17 by a direct translational repression. Further, in both melanoma cell lines ETV1 knockdown by selective siRNA successfully pheno-copies the facilitated cell migration, while overexpression of ETV1 inhibits cell motility and migration. Altered ETV1 expression does not affect melanoma net-proliferation. In conclusion, we show a new role for miR-17 in melanoma, facilitating cell motility, by targeting the translation of ETV1 protein, which may support the development of metastasis.

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Section: Discussionmentioning

confidence: 99%

miR-17 regulates melanoma cell motility by inhibiting the translation of ETV1

et al. 2015

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“…16 hours after plating, cells were transfected with miR-497 (1 pmol / well) or non-targeting siRNA (1 pmol / well), pRSV-βgal (constitutive β-galactosidase expression vector; 70 ng / well), and an appropriate luciferase reporter plasmid (30 ng / well) using Lipofectamine 2000 (Life Technologies) per manufacturer's protocol. Luciferase activity was measured and normalized for that of β-galactosidase as described before [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade

et al. 2015

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It is increasingly clear that the biological functions of a transcription factor cannot be fully understood solely on the basis of protein-coding genes that fall under its control. Many transcription factors regulate expression of miRNAs, which affect the cell by modulating translation and stability of mRNAs. The identities and the roles of NF-κB-regulated miRNAs have been attracting research interest for a long time. We revisited this issue in a system with controlled expression of one of the key regulators of NF-κB, RIPK1. Several regulated miRNAs were identified, including miR-146a, miR-215 and miR-497. The miRNAs were also inducible by IL-1β, but not when NF-κB activity was repressed by mutant IκBα. The presence of a miR-497 site was predicted in the 3′-UTR of IKBKB gene, which encodes IKKβ. Using appropriately engineered reporters, we confirmed that this site can be a target of suppressive action of miR-497. Our findings suggest that NF-κB controls expression of a miRNA, which may reduce production of IKKβ. Considering the role of IKKβ in the canonical pathway of NF-κB activation, our observations may indicate a new mechanism that modulates the magnitude of such activation, as well as the propensity of a cell to engage canonical vs. non-canonical pathways.

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“…Prostate-specific antigen (PSA) expression is also enhanced by ETV1 (Gasi, 2014). We currently have a limited understanding of how molecular pathways are affected by elevated ETV1 levels in prostate cancer (Gasi, 2014; Zynda, 2013). …”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of <I>β</I>-Catenin Signaling Pathway Inactivation in ETV1-Positive Prostate Cancers

Morsalin

Yang

Fang

et al. 2015

j pharmaceut sci pharmacol

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In the United States of America, prostate cancer is the second most common age-related cancer among men. African-American men have the highest incidence of, and mortality rate from this disease in the United States. According to the American Cancer Society, 29% of all cancer cases and 9% of all cancer deaths are a result of prostate cancer. Individuals who are at highest risk include African-American men, men over 60 years of age, and those with a family history of the disease. African-Americans also have twice the risk of developing prostate cancer as compared to Caucasians. Erythroblastosis virus E26 transformation-specific (ETS) factors play an important role in human cancers. ETS Variant 1 (ETV1), an ETS factor, is notable for its association in prostate cancers, where truncated ETV1 (dETV1) or its full length counterpart is overexpressed in approximately 10% of the prostate cancer patients. Prostate cancer tumorigenesis may be initiated by deregulation of the Wnt/β-catenin pathway. Mutations that stabilize β-catenin were shown to contribute to the loss of cell-growth control in tumorigenesis. We hypothesized that ETV1’s interaction with components of the Wnt/β-catenin pathway may alter β-catenin’s interaction with downstream tumor-suppressor genes, which are critical in regulating apoptosis and cell-growth properties of prostate cells. Our results demonstrate for the first time that ETV1 alters β-catenin activity by activating kinases that regulate Wnt/β-catenin activity through post-translational modification in prostate cancer cells. We further demonstrate that therapeutic agents such as PD98059, that reverse effect of ETV1 on Wnt/β-catenin signaling pathway, can be used to target ETV1-positive prostate cancer cells. These therapeutic agents could have a profound impact on prevention and treatment of prostate cancer which may help to reduce health disparity seen in minority patients. Understanding the role of ETV1 in Wnt/β-catenin pathway will also allow us to develop better diagnostic tools, which can be used as a biomarker for ETV1-positive prostate cancers.

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ETV1 positively regulates transcription of tumor suppressor ARF

Cited by 3 publications

References 53 publications

miR-17 regulates melanoma cell motility by inhibiting the translation of ETV1

miR-17 regulates melanoma cell motility by inhibiting the translation of ETV1

MicroRNA analysis suggests an additional level of feedback regulation in the NF-κB signaling cascade

Molecular Mechanism of <I>β</I>-Catenin Signaling Pathway Inactivation in ETV1-Positive Prostate Cancers

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