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:
Notes: --- - "Export Date: 1 April 2013" - "CODEN: JPTLA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Qianxing Mo
    37 Mo
  2. Marick E. Lae
    15 Lae
  3. Tsuyoshi Saito
    22 Saito
  4. Makoto Nagai
    6 Nagai
  5. Masumi Tsuda
    6 Tsuda
  6. Marc Ladanyi
    848 Ladanyi
  7. Adam B Olshen
    107 Olshen
  8. Christophe Antczak
    40 Antczak
  9. Christina Leslie
    106 Leslie
  10. Rachel Kobos
    65 Kobos