Histone Deacetylase 1 Can Repress Transcription by Binding to Sp1

Abstract

The chromatin of eukaryotic cells is organized in nucleosomes. This organization allows the efficient packaging of chromosomal DNA into the nucleus but limits the access of highmolecular-weight protein complexes of the transcription machinery. At least two different mechanisms enable the eukaryotic cell to relieve nucleosomal repression: the chromatinremodeling complexes (reviewed in references 55 and 57) and reversible histone acetylation. Two recent reports indicate a direct link between these two activities (60, 67). Posttranslational acetylation on conserved lysine residues within the Nterminal regions of nucleosomal histones is assumed to lead to a reduced attraction between chromosomal DNA and histone tails and changed interactions with neighboring nucleosomes or other nonhistone proteins. The resulting local chromatin decondensation increases the accessibility of particular DNA regions for RNA polymerase complexes. Consistent with this idea, transcriptionally active chromatin correlates with histone hyperacetylation (reviewed in references 18, 30, 47, 49, 61, and 62). This model predicts that histone acetyltransferases would promote transcription, while histone deacetylases (HDACs) should act as repressors. In accordance with this model, several transcriptional adapters and coactivators, such as GCN5 (8, 31), p300/CBP (4, 46), TAFII250 (40), SRC-1 (54), and ACTR (10), have been classified as histone acetyltransferases. Five HDACs have been identified in mammalian cells (12,14,56,58,63,64). Three of them, HDAC1, HDAC2, and HDAC3, have significant homology to yeast Rpd3 (44,50,59). HDAC4 and HDAC5 belong to the histone deacetylase A (HDA) family (9, 58). HDAC1 and HDAC2 are found in high-molecularweight complexes associated with adapter proteins like SIN3, SAP18, and SAP30 and nuclear corepressors like N-CoR, SMRT, and 24,32,42,65,66). Recently it was demonstrated that several mammalian transcription factors, such as Mad (21, 24, 32, 52), YY1 (64), hormone-dependent nuclear receptors (24, 42), MeCP2 (26, 43), CBF (27), retinoblastoma protein (Rb) (7, 38, 39), and related pocket proteins (16), can repress transcription by recruiting HDACs to specific promoters. In addition, the aberrant recruitment of HDACs by PLZF, PML, and ETO fusion proteins can interfere with the differentiation of hematopoietic precursor cells in acute promyelocytic leukemia (13,17,19,35).In this study we investigated the potential function of HDACs as transcriptional repressors during the growth arrest of mammalian cells. Using the S-phase-specific mouse thymidine kinase (TK) promoter as a model system, we show that HDAC1 can mediate transcriptional repression via the Sp1 binding site. HDAC1 is associated with Sp1 and binds directly to the C-terminal part of Sp1 that was previously identified as interacting domain for E2F1 (28). Sp1 and E2F1 cooperate in the activation of S-phase-specific promoters (28, 36). Here we show that E2F1 but not E2F4 can compete with HDAC1 binding to Sp1, thereby relieving HDAC1-mediated repression of the TK...

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

“…Endogenous Sp1 was immunoprecipitated from protein lysates of HeLa cells transfected with HDAC4/FLAG with a Sp1-specific antibody and the bound protein complexes were analysed by western blot. Sp1 interacted with HDAC4 and HDAC1 but not with HDAC3 (Figure 4e), as reported (Doetzlhofer et al, 1999;Sun et al, 2002;Kang et al, 2005;Enya et al, 2008). Co-immunoprecipitation with anti-FLAG antibody confirmed the physical HDAC4 silencing inhibits cell proliferation in vitro and inhibits tumor growth in vivo Because p21 WAF1/Cip1 is a cyclin-dependent kinase inhibitor that blocks the G1/S-phase transition and cell proliferation, the repression of p21 WAF1/Cip1 transcription in cancer cells by HDAC4 suggests a key role for HDAC4 in cancer cells proliferation and tumor growth.…”

“…As HDAC3 silencing did not increase p21 WAF1/Cip1 expression in IGROV-1 cells (Figure 1b), it is also possible that the mechanism by which HDAC4 represses the p21 WAF1/Cip1 promoter varies between cell types. We found that Sp1 physically associates with HDAC4 and HDAC1, but does not interact with HDAC3 as reported (Doetzlhofer et al, 1999;Sun et al, 2002;Davie, 2003;He et al, 2005;Kang et al, 2005). We therefore speculate that HDAC4 participates, with a HDAC1-dependent co-repressor complex, in p21 WAF1/Cip1 repression.…”

Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy

“…55,57 Histone deacetylase-1 inhibitors have been shown to enhance the transcription activity of promoters in a variety of cellular and viral genes containing Sp1-binding sites. [58][59][60][61][62] Sp1 belongs to the Sp family of transcription factors (Sp1-Sp4) that bind to the same consensus sequences (GGGCGG). 63 As other factors can also interact with Sp1, competition between transcription factors and HDACs may represent a general way to regulate gene expression via reversible modifications of chromatin structure.…”

Regulation of Ets function by protein–protein interactions

“…Similarly, it is known that Rb, which interacts with Elf1, physically interacts with histone deacetylase HDAC1 (MagnaghiJaulin et al, 1998). Another example is Sp1, which interacts with many Ets factors (Block et al, 1996;Dittmer et al, 1997;Eichbaum et al, 1997;Krehan et al, 2000)), and has been shown to interact with HDAC1 (Doetzlhofer et al, 1999), repressing transcription. TEL is able to recruit co-repressors such as SMRT and mSin3A resulting in transcriptional repression Fenrick et al, 1999).…”