title: 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 14-3-3σ, 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-7, which regulate extracellular matrix in the prostate tumor microenvironment. S216 mutation or 14-3-3τ downregulation was sufficient to reduce ETV1 protein levels in prostate cancer cells, indicating that non-σ 14-3-3 proteins protect ETV1 from degradation. Notably, S216 mutation also decreased ETV1-dependent migration and invasion in benign prostate cells. Downregulation of 14-3-3τ reduced prostate cancer cell invasion and growth in the same manner as ETV1 attenuation. Finally, we showed that 14-3-3τ and 14-3-3ε were overexpressed in human prostate tumors. Taken together, our results showed that non-σ 14-3-3 proteins are important modulators of ETV1 function that promote prostate tumorigenesis.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Sangphil
authors.initials: S
authors.lastname: Oh
authors.forename: Sook
authors.initials: S
authors.lastname: Shin
authors.forename: Stan A
authors.initials: SA
authors.lastname: Lightfoot
authors.forename: Ralf
authors.initials: R
authors.lastname: Janknecht
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005095:Exoribonucleases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D005095:Exoribonucleases; C413442:SFN protein, human; D020783:Matrix Metalloproteinase 7; D020781:Matrix Metalloproteinase 1