The TFG-TEC oncoprotein induces transcriptional activation of the human β-enolase gene via chromatin modification of the promoter region

Mol Carcinog. 2016 Oct;55(10):1411-23. doi: 10.1002/mc.22384. Epub 2015 Aug 27.

Abstract

Recurrent chromosome translocations are the hallmark of many human cancers. A proportion of human extraskeletal myxoid chondrosarcomas (EMCs) are associated with the characteristic chromosomal translocation t(3;9)(q11-12;q22), which results in the formation of a chimeric protein in which the N-terminal domain of the TRK-fused gene (TFG) is fused to the translocated in extraskeletal chondrosarcoma (TEC; also called CHN, CSMF, MINOR, NOR1, and NR4A3) gene. The oncogenic effect of this translocation may be due to the higher transactivation ability of the TFG-TEC chimeric protein; however, downstream target genes of TFG-TEC have not yet been identified. The results presented here, demonstrate that TFG-TEC activates the human β-enolase promoter. EMSAs, ChIP assays, and luciferase reporter assays revealed that TFG-TEC upregulates β-enolase transcription by binding to two NGFI-B response element motifs located upstream of the putative transcription start site. In addition, northern blot, quantitative real-time PCR, and Western blot analyses showed that overexpression of TFG-TEC up-regulated β-enolase mRNA and protein expression in cultured cell lines. Finally, ChIP analyses revealed that TFG-TEC controls the activity of the endogenous β-enolase promoter by promoting histone H3 acetylation. Overall, the results presented here indicate that TFG-TEC triggers a regulatory gene hierarchy implicated in cancer cell metabolism. This finding may aid the development of new therapeutic strategies for the treatment of human EMCs. © 2015 Wiley Periodicals, Inc.

Keywords: TFG-TEC; chromosomal translocation; fusion protein; human extraskeletal myxoid chondrosarcoma; human β-enolase gene; transcription activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Chondrosarcoma / genetics*
  • Chondrosarcoma / metabolism
  • Chromatin / metabolism
  • Chromosomes, Human, Pair 3 / genetics
  • Chromosomes, Human, Pair 9 / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Neoplasms, Connective and Soft Tissue / genetics*
  • Neoplasms, Connective and Soft Tissue / metabolism
  • Oncogene Proteins, Fusion / metabolism*
  • Phosphopyruvate Hydratase / chemistry
  • Phosphopyruvate Hydratase / genetics*
  • Phosphopyruvate Hydratase / metabolism
  • Promoter Regions, Genetic*
  • Proteins / genetics
  • Proteins / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Transcriptional Activation*
  • Translocation, Genetic

Substances

  • Chromatin
  • DNA-Binding Proteins
  • NR4A3 protein, human
  • Oncogene Proteins, Fusion
  • Proteins
  • Receptors, Steroid
  • Receptors, Thyroid Hormone
  • TFG protein, human
  • Phosphopyruvate Hydratase

Supplementary concepts

  • Chondrosarcoma, Extraskeletal Myxoid