Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases

Abstract

The Sir2 histone deacetylase gene family consists of seven mammalian sirtuins (SIRTs) which are NAD-dependent histone/protein deacetylases. Sir2 proteins regulate, for instance, genome stability by chromatin silencing in yeast. In mammals, their function is still largely unknown. Due to the NAD+ dependency, Sir2 might be the link between metabolic activity and histone/protein acetylation. Regulation of gene expression also seems to play an important role in Sir2 functions, since increasing the dosage of Sir2 genes increases genome stability in yeast and Caenorhabditis elegans. We observed that the modification of histone/protein acetylation status by several class I and II histone deacetylase (HDAC) inhibitors induces differential changes in gene expression profiles of seven SIRT mRNAs in cultured neuronal cells. SIRT2, SIRT4 and SIRT7 were upregulated, whereas SIRT1, SIRT5 and SIRT6 were downregulated by trichostatin A (TSA) and n-butyrate. The upregulation of SIRT mRNAs was inhibited by actinomycin D. Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neuroblastoma cells and post-mitotic rat primary hippocampal and cerebellar granule neurons. Using a chromatin immunoprecipitation technique, we showed that the upregulation of SIRT2 expression with TSA is related to the hyperacetylation of DNA-bound histone H4 within the first 500 bp upstream of the transcription start site of the SIRT2 gene. Chemically different types of HDAC inhibitors, such as TSA, apicidin, SAHA, M344 and n-butyrate induced remarkably similar responses in SIRT1-7 mRNA expression patterns. Differential responses in SIRT mRNA expression profiles indicate that the expression of the Sir2 family of genes is selectively regulated and dependent on histone/protein acetylation status.

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

“…In keeping with our findings that findings that SIRT 2, 4 and 7 expression is directly upregulated by VPA and by TSA, it has previously been reported that several different inhibitors of class I and II deacetylases increase expression of SIRT2, 4 and 7 (Kyrylenko et al, 2003). We therefore reasoned that blocking activity of the sirtuins should preclude TSA or VPA mediated downregulation of ERa; however, treatment of MCF-7 cells for 16 h with sirtinol, an inhibitor of the sirtuins (Grozinger et al, 2001), induced loss of ERa (Figure 6b).…”

“…A second type of deacetylase activity, the sirtuins, also exists. These are NAD-dependent deacetylases that are not significantly inhibited by either TSA or by VPA (Kyrylenko et al, 2003) and have been shown to have significant roles in transcriptional repression, cell morphology and in determining longevity.…”

Histone deacetylase (HDAC) encoding gene expression in pancreatic cancer cell lines and cell sensitivity to HDAC inhibitors

“…Indeed, in the case of culture neuronal cells, it has been shown that modification of histone/protein acetylation status by TSA, n-butyrate, suberoylanilide hydroxamid (SAHA), apicidin and M344 induced an upregulation of SIRT2, SIRT4 and SIRT7 genes, whereas SIRT1, SIRT5 and SIRT6 were downregulated. 28 Therefore, treatment with HDIs may result in complex molecular interactions that modulate the expression of various tumor relevant genes that play significant roles in the cell cycle progression or apoptosis.…”

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

“…Further, HDACs 1-8 were ubiquitously expressed in H157 cells as assessed by immunoblotting, and did not show any change in expression after VPA or TSA exposure (data not shown). VPA and TSA indeed bind directly to and inhibit class I and class II HDACs, but importantly these molecules have also been shown to affect class III sirtuin deacetylases indirectly, including SIRT1, in mammalian cells by regulating their gene expression (Kyrylenko et al, 2003;KW and OH, unpublished observations). We therefore examined the effects of TSA and VPA exposure on SIRT1 protein levels ( Figure 5a).…”