SYT-SSX1 and SYT-SSX2 interfere with repression of E-cadherin by snail and slug: A potential mechanism for aberrant mesenchymal to epithelial transition in human synovial sarcoma Journal Article

  

Authors:	Saito, T.; Nagai, M.; Ladanyi, M.
Article Title:	SYT-SSX1 and SYT-SSX2 interfere with repression of E-cadherin by snail and slug: A potential mechanism for aberrant mesenchymal to epithelial transition in human synovial sarcoma
Abstract:	Synovial sarcoma is a primitive mesenchymal neoplasm characterized in almost all cases by a t(X;18) fusing the SYT transcriptional coactivator gene with either SSX1 or SSX2, with the resulting fusion gene encoding an aberrant transcriptional regulator. A subset of synovial sarcoma, predominantly cases with the SYT-SSX1 fusion, shows foci of morphologic epithelial differentiation in the form of nests of glandular epithelium. The striking spontaneous mesenchymal to epithelial differentiation in this cancer is reminiscent of a developmental switch, but the only clue to its mechanistic basis has been the observation that most cases of synovial sarcoma with glandular epithelial differentiation (GED) contain SYT-SSX1 instead of SYT-SSX2. We report here that SYT-SSX1 and SYT-SSX2 interact preferentially with Snail or Slug, respectively, and prevent these transcriptional repressors from binding to the proximal E-cadherin promoter as shown by coimmunoprecipitation and chromatin immunoprecipitation. Luciferase reporter assays reveal that SYT-SSX1 and SYT-SSX2 can respectively overcome the Snail- or Slug-mediated repression of E-cadherin transcription. This provides a mechanism by which E-cadherin expression, a prerequisite of epithelial differentiation, is aberrantly derepressed in synovial sarcoma and may also explain the association of GED with the SYT-SSX1 fusion because it interferes with Snail, the stronger repressor of the E-cadherin promoter. Thus, our data provide a mechanistic basis for the observed heterogeneity in the acquisition of epithelial characteristics in synovial sarcoma and highlight the potential role of differential interactions with Snail or Slug in modulating this phenotypic transition. ©2006 American Association for Cancer Research.
Keywords:	controlled study; protein expression; unclassified drug; human cell; promoter region; protein domain; protein protein interaction; luciferase; protein binding; transcription factor; cell differentiation; transcription, genetic; cancer cell culture; cell line, tumor; hela cells; transfection; uvomorulin; transcription factors; cell heterogeneity; transcription regulation; amino acid sequence; molecular sequence data; hybrid protein; chromatin immunoprecipitation; gene fusion; oncogene proteins, fusion; transactivation; epithelial cells; synovial sarcoma; sarcoma, synovial; transcription factor slug; cadherins; transcription factor snail; mesoderm; promoter regions (genetics); trans-activation (genetics); transcription factor ssx 1; transcription factor ssx 2; transcription factor syt
Journal Title:	Cancer Research
Volume:	66
Issue:	14
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2006-07-15
Start Page:	6919
End Page:	6927
Language:	English
DOI:	10.1158/0008-5472.can-05-3697
PUBMED:	16849535
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33746906998&partnerID=40&md5=1911b73bb4c078c6d7859194af5f03ab
Notes:	--- - "Cited By (since 1996): 30" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/27993