Document Detail


Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein.
MedLine Citation:
PMID:  23288701     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Oncogenic rearrangements of the TFE3 transcription factor gene are found in two distinct human cancers. These include ASPSCR1-TFE3 in all cases of alveolar soft part sarcoma (ASPS) and ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3 and others in a subset of paediatric and adult RCCs. Here we examined the functional properties of the ASPSCR1-TFE3 fusion oncoprotein, defined its target promoters on a genome-wide basis and performed a high-throughput RNA interference screen to identify which of its transcriptional targets contribute to cancer cell proliferation. We first confirmed that ASPSCR1-TFE3 has a predominantly nuclear localization and functions as a stronger transactivator than native TFE3. Genome-wide location analysis performed on the FU-UR-1 cell line, which expresses endogenous ASPSCR1-TFE3, identified 2193 genes bound by ASPSCR1-TFE3. Integration of these data with expression profiles of ASPS tumour samples and inducible cell lines expressing ASPSCR1-TFE3 defined a subset of 332 genes as putative up-regulated direct targets of ASPSCR1-TFE3, including MET (a previously known target gene) and 64 genes as down-regulated targets of ASPSCR1-TFE3. As validation of this approach to identify genuine ASPSCR1-TFE3 target genes, two up-regulated genes bound by ASPSCR1-TFE3, CYP17A1 and UPP1, were shown by multiple lines of evidence to be direct, endogenous targets of transactivation by ASPSCR1-TFE3. As the results indicated that ASPSCR1-TFE3 functions predominantly as a strong transcriptional activator, we hypothesized that a subset of its up-regulated direct targets mediate its oncogenic properties. We therefore chose 130 of these up-regulated direct target genes to study in high-throughput RNAi screens, using FU-UR-1 cells. In addition to MET, we provide evidence that 11 other ASPSCR1-TFE3 target genes contribute to the growth of ASPSCR1-TFE3-positive cells. Our data suggest new therapeutic possibilities for cancers driven by TFE3 fusions. More generally, this work establishes a combined integrated genomics/functional genomics strategy to dissect the biology of oncogenic, chimeric transcription factors.
Authors:
Rachel Kobos; Makoto Nagai; Masumi Tsuda; Man Yee Merl; Tsuyoshi Saito; Marick Laé; Qianxing Mo; Adam Olshen; Steven Lianoglou; Christina Leslie; Irina Ostrovnaya; Christophe Antczak; Hakim Djaballah; Marc Ladanyi
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-05
Journal Detail:
Title:  The Journal of pathology     Volume:  229     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-02     Revised Date:  2014-07-28    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  743-54     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*,  metabolism
COS Cells
Cell Nucleus / metabolism
Cell Proliferation
Cell Survival
Cercopithecus aethiops
Chromatin Immunoprecipitation
Cluster Analysis
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Fusion*
Genes, Reporter
Genomics* / methods
Genotype
HEK293 Cells
HeLa Cells
High-Throughput Screening Assays
Humans
MCF-7 Cells
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Fusion / genetics*,  metabolism
Phenotype
Promoter Regions, Genetic
RNA Interference
Reproducibility of Results
Sarcoma, Alveolar Soft Part / genetics*,  metabolism,  pathology
Transcriptional Activation
Transfection
Grant Support
ID/Acronym/Agency:
5 P30 CA008748-44/CA/NCI NIH HHS; CA95785/CA/NCI NIH HHS; P30 CA008748/CA/NCI NIH HHS; R01 CA095785/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/ASPSCR1 protein, human; 0/Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; 0/Oncogene Proteins, Fusion; 0/TFE3 protein, human

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