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FAM129B is a novel regulator of Wnt/?-catenin signal transduction in melanoma cells.

ABSTRACT: The inability of targeted BRAF inhibitors to produce long-lasting improvement in the clinical outcome of melanoma highlights a need to identify additional approaches to inhibit melanoma growth. Recent studies have shown that activation of the Wnt/?-catenin pathway decreases tumor growth and cooperates with ERK/MAPK pathway inhibitors to promote apoptosis in melanoma. Therefore, the identification of Wnt/?-catenin regulators may advance the development of new approaches to treat this disease. In order to move towards this goal we performed a large scale small-interfering RNA (siRNA) screen for regulators of ?-catenin activated reporter activity in human HT1080 fibrosarcoma cells. Integrating large scale siRNA screen data with phosphoproteomic data and bioinformatics enrichment identified a protein, FAM129B, as a potential regulator of Wnt/?-catenin signaling. Functionally, we demonstrated that siRNA-mediated knockdown of FAM129B in A375 and A2058 melanoma cell lines inhibits WNT3A-mediated activation of a ?-catenin-responsive luciferase reporter and inhibits expression of the endogenous Wnt/?-catenin target gene, AXIN2. We also demonstrate that FAM129B knockdown inhibits apoptosis in melanoma cells treated with WNT3A. These experiments support a role for FAM129B in linking Wnt/?-catenin signaling to apoptosis in melanoma.

SUBMITTER: Conrad W

PROVIDER: S-EPMC3829391 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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FAM129B is a novel regulator of Wnt/β-catenin signal transduction in melanoma cells.

Conrad Willliam W Major Michael B MB Cleary Michele A MA Ferrer Marc M Roberts Brian B Marine Shane S Chung Namjin N Arthur William T WT Moon Randall T RT Berndt Jason D JD Chien Andy J AJ

F1000Research 20130531

The inability of targeted BRAF inhibitors to produce long-lasting improvement in the clinical outcome of melanoma highlights a need to identify additional approaches to inhibit melanoma growth. Recent studies have shown that activation of the Wnt/β-catenin pathway decreases tumor growth and cooperates with ERK/MAPK pathway inhibitors to promote apoptosis in melanoma. Therefore, the identification of Wnt/β-catenin regulators may advance the development of new approaches to treat this disease. In ...[more]

PMID: 24358901

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Project description:BackgroundMore than the two decades, the question of whether vitamin D has a role in cancer frequency, development, and death has been premeditated in detail. Colorectal, breast, and prostate cancers have been a scrupulous spot of center, altogether, these three malignancies report for approximately 35% of cancer cases and 20% of cancer demises in the United States, and as such are a chief public health apprehension. The aim was to evaluate antitumor activity of Vitamin D-Nanoemulsion (NVD) in colorectal cancer cell lines and HCT116 xenograft model in a comprehensive approach.MethodsTwo human colorectal cancer cell lines HCT116 and HT29 (gained from College of Pharmacy, King Saud University, KSA were grown. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazoliumbromide protocol were performed to show the impact of NVD and β-catenin inhibitor (FH535) on the viability of HCT116 and HT29 cell lines. Apoptosis/cell cycle assay was performed. Analysis was done with a FACScan (Becton-Dickinson, NJ). About 10,000 cells per sample were harvested and Histograms of DNA were analyzed with ModiFitLT software (verity Software House, ME, USA). Western blotting and RT-PCR were performed for protein and gene expression respectively in in vitro and in vivo.ResultsWe found that NVD induced cytotoxicity in colorectal cells in a dose-dependent manner and time dependent approach. Further, our data validated that NVD administration of human colorectal cancer HCT116 and HT29 cells resulted in cell growth arrest, alteration in molecules regulating cell cycle operative in the G2 phase of the cell cycle and apoptosis in a dose dependent approach. Further our results concluded that NVD administration decreases expression of β-catenin gene, AKT gene and Survivin gene and protein expression in in vitro and in vivo.ConclusionOur findings suggest that targeting β-catenin gene may encourage the alterations of cell cycle and cell cycle regulators. Wnt/β-catenin signaling pathway possibly takes part in the genesis and progression of colorectal cancer cells through regulating cell cycle and the expression of cell cycle regulators.

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FAM129B is a novel regulator of Wnt/?-catenin signal transduction in melanoma cells.

Publications

FAM129B is a novel regulator of Wnt/β-catenin signal transduction in melanoma cells.

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