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14-3-3 proteins modulate the ETS transcription factor ETV1 in prostate cancer.

ABSTRACT: Overexpression of the ETS-related transcription factor ETV1 can initiate neoplastic transformation of the prostate. ETV1 activity is highly regulated by phosphorylation, but the underlying mechanisms are unknown. Here we report that all 14-3-3 proteins, with the exception of the tumor suppressor 14-3-3?, can bind to ETV1 in a condition manner dictated by its prominent phosphorylation site S216. Non-? 14-3-3 proteins synergized with ETV1 to activate transcription of its target genes MMP-1 and MMP-7, which regulate extracellular matrix in the prostate tumor microenvironment. S216 mutation or 14-3-3? downregulation was sufficient to reduce ETV1 protein levels in prostate cancer cells, indicating that non-? 14-3-3 proteins protect ETV1 from degradation. Notably, S216 mutation also decreased ETV1-dependent migration and invasion in benign prostate cells. Downregulation of 14-3-3? reduced prostate cancer cell invasion and growth in the same manner as ETV1 attenuation. Finally, we showed that 14-3-3? and 14-3-3? were overexpressed in human prostate tumors. Taken together, our results showed that non-? 14-3-3 proteins are important modulators of ETV1 function that promote prostate tumorigenesis.

SUBMITTER: Oh S

PROVIDER: S-EPMC3745528 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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14-3-3 proteins modulate the ETS transcription factor ETV1 in prostate cancer.

Oh Sangphil S Shin Sook S Lightfoot Stan A SA Janknecht Ralf R

Cancer research 20130617 16

Overexpression of the ETS-related transcription factor ETV1 can initiate neoplastic transformation of the prostate. ETV1 activity is highly regulated by phosphorylation, but the underlying mechanisms are unknown. Here we report that all 14-3-3 proteins, with the exception of the tumor suppressor 14-3-3σ, can bind to ETV1 in a condition manner dictated by its prominent phosphorylation site S216. Non-σ 14-3-3 proteins synergized with ETV1 to activate transcription of its target genes MMP-1 and MMP ...[more]

PMID: 23774214

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Project description:The ETS-transcription factor ETV1 is involved in epithelial-mesenchymal transition during pancreatic development and is induced in mouse pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). We investigated the function of ETV1 in stromal expansion of PDAC and metastasis, as well as its effects on a novel downstream target Sparc, which encodes a matricellular protein found in PDAC stroma that has been associated with invasiveness, metastasis and poor patient outcomes.Pancreatic ductal cells were isolated from Pdx1Cre;Kras(G12D/+) mice (PanIN), Pdx1Cre;Kras(G12D/+);p53(fl/+) and Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP) mice (PDAC), and Pdx1Cre;Kras(G12D/+);p53(fl/+);Sparc(-/-) mice. Cells were grown in 3-dimensional organoid culture to analyze morphology, proliferation, and invasion. Human PanIN and PDAC tissues were evaluated for ETV1 expression. Orthotopic pancreatic transplants of ETV1-overexpressing PDAC and respective control cells were performed.ETV1 expression was significantly increased in human PanINs and, even more so, in primary and metastatic PDAC. Analyses of mouse orthotopic xenografts revealed that ETV1 induced significantly larger primary tumors than controls, with significantly increased stromal expansion, ascites and metastases. In 3-dimensional organoids, ETV1 disrupted cyst architecture, induced EMT, and increased invasive capacity. Furthermore, we identified Sparc as a novel functional gene target of Etv1 by luciferase assays, and SPARC and ETV1 proteins co-localized in vivo. Disruption of Sparc abrogates the phenotype of stromal expansion and metastasis found with ETV1 overexpression in vivo. We identified hyaluronan synthase 2 (Has2) as another novel downstream factor of Etv1; that may mediate ETV1's significant expansion of hyaluronic acid in PDAC stroma. Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP);Cre;Etv1(fl/fl)) reduced levels of SPARC and hyaluronic acid in the stroma.ETV1 is critical in the desmoplastic stromal expansion and metastatic progression of pancreatic cancer in mice, mediated functionally in part through Sparc and Has2.

Dataset Information

14-3-3 proteins modulate the ETS transcription factor ETV1 in prostate cancer.

Publications

14-3-3 proteins modulate the ETS transcription factor ETV1 in prostate cancer.

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