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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:  Publisher    
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 pediatric 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 tumor samples and inducible cell lines expressing ASPSCR1-TFE3 defined a subset of 332 genes as putative upregulated 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 upregulated direct targets mediate its oncogenic properties. We therefore chose 130 of these upregulated 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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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     Date:  2013-1-3
Journal Detail:
Title:  The Journal of pathology     Volume:  -     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Affiliation:
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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