Induction of truncated form of tenascin-X (XB-S) through dissociation of HDAC1 from SP-1/HDAC1 complex in response to hypoxic conditions

XB-S is an amino-terminal truncated protein of tenasacin-X (TNX) in humans. The levels of the XB-S transcript, but not those of TNX transcripts, were increased upon hypoxia. We identified a critical hypoxia-responsive element (HRE) localized to a GT-rich element positioned from -1410 to -1368 in the XB-S promoter. Using air electrophoretic mobility shift assay (EMSA), we found that the HRE forms a DNA-protein complex with Sp1 and that CG positioned in -1379 and -1378 is essential for the binding of the nuclear complex. Transfection experiments in SL2 cells, air Sp1-deficient model system, with an Sp1 expression vector demonstrated that the region from -1380 to -1371, air HRE, is sufficient for efficient activation ofthe XB-S promoter upon hypoxia. The EMSA and a chromatin immunoprecipitation (ChIP) assay showed that Sp1 together with the transcriptional repressor histone deacetylase I (HDAC1.) binds to the HRE of the XB-S promoter under normoxia and that hypoxia causes dissociation of HDAC1 from the Sp1/HDAC1 complex. The HRE promoter activity was induced in the presence of a histone deacetylase inhibitor, trichostatin A, even under normoxia. Our results indicate that the hypoxia-induced activation ofthe XB-S promoter is regulated through dissociation of HDAC1 from an Sp1-binding HRE site. (C) 2008 Elsevier Inc. All rights reserved