Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein Journal Article

   

Authors:	Kobos, R.; Nagai, M.; Tsuda, M.; Merl, M. Y.; Saito, T.; Lae, M.; Mo, Q.; Olshen, A.; Lianoglou, S.; Leslie, C.; Ostrovnaya, I.; Antczak, C.; Djaballah, H.; Ladanyi, M.
Article Title:	Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein
Abstract:	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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords:	uridine phosphorylase; alveolar soft part sarcoma; tfe3; chromosomal translocation; renal carcinoma; cyp17a1; aspscr1; nampt
Journal Title:	Journal of Pathology
Volume:	229
Issue:	5
ISSN:	0022-3417
Publisher:	Wiley Blackwell
Date Published:	2013-04-01
Start Page:	743
End Page:	754
Language:	English
DOI:	10.1002/path.4158
PROVIDER:	scopus
PUBMED:	23288701
PMCID:	PMC4083568
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84875054627&partnerID=40&md5=a6300e5bac52d1ae62d2a9527f3fd1c9
Notes:	--- - "Export Date: 1 April 2013" - "CODEN: JPTLA" - "Source: Scopus"

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