The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation

Abstract

Histone deacetylases (HDACs) are chromatin-modifying enzymes that are involved in the regulation of proliferation, differentiation and development. HDAC inhibitors induce cell cycle arrest, differentiation, or apoptosis in tumor cells and are therefore promising antitumor agents. Numerous genes were found to be deregulated upon HDAC inhibitor treatment; however, the relevant target enzymes are still unidentified. HDAC1 is required for mouse development and unrestricted proliferation of embryonic stem cells. We show here that HDAC1 reversibly regulates cellular proliferation and represses the cyclin-dependent kinase inhibitor p21 in embryonic stem cells. Disruption of the p21 gene rescues the proliferation phenotype of HDAC1 ؊/؊ embryonic stem cells but not the embryonic lethality of HDAC1 ؊/؊ mice. In the absence of HDAC1, mouse embryonic fibroblasts scarcely undergo spontaneous immortalization and display increased p21 expression. Chromatin immunoprecipitation assays demonstrate a direct regulation of the p21 gene by HDAC1 in mouse embryonic fibroblasts. Transformation with simian virus 40 large T antigen or ablation of p21 restores normal immortalization of primary HDAC1؊/؊ fibroblasts. Our data demonstrate that repression of the p21 gene is crucial for HDAC1-mediated control of proliferation and immortalization. HDAC1 might therefore be one of the relevant targets for HDAC inhibitors as anticancer drugs.Acetylation of core histones is linked to the opening of chromatin and transcriptional activation. Modification of lysine residues by acetylation is thought to affect gene expression either by altering the affinity of histones to the DNA, or by creating binding sites for detector proteins that regulate chromatin accessibility. The antagonistic activities of two types of enzymes, histone acetyltransferases and histone deacetylases (HDACs), control the reversible acetylation state at the Nterminal tail of histones. HDACs catalyze the removal of the acetyl moieties from acetylated histones and other proteins and are in general associated with transcriptional repression (17). Based on their homologies with yeast deacetylases mammalian HDACs have been classified into Rpd3-like (class I), Hda1-like (class II), and Sir2-like (class III) enzymes (19). HDAC11 seems to represent a class (class IV) on its own.HDACs have been shown to regulate many important biological processes, including cell cycle progression, differentiation, and development. In agreement with this idea, HDAC inhibitor treatment leads to cell cycle arrest, differentiation, and apoptosis in cultured tumor cells and tumors in animal models. Therefore, several HDAC inhibitors are currently tested as antitumor drugs in clinical trials. A variety of HDAC inhibitors, which target class I and class II enzymes have been identified (33), and it has been shown that they exert their antiproliferative effects via transcriptional and nontranscriptional mechanisms (32). Treatment of untransformed cells with HDAC inhibitors triggers a G 2 checkpoint resulting in arr...

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells

“…S1B), the majority of cells remained viable. A loss of cell proliferation is a common phenotype in all Hdac1/2 knockout (18,23,33,34) and knockdown (35) studies. In each case, loss of HDAC1/2 is associated with up-regulation of the cyclin-dependent kinase inhibitor, p21 WAF1/CIP1 , which limits G 1 -to S-phase transition.…”

Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21

“…Histone marks, such as trimethyl H3K27, which indicates repressed p21 expression (44), could also affect chromatin structure altered by parthenolide. Another epigenetic player, HDAC1, was recently shown to regulate cellular proliferation and differentiation by directly targeting the p21 gene, as shown by ChIP assays (45). Interestingly, parthenolide is the first example of small molecules that specifically inhibits HDAC1 without affecting other HDACs, possibly resulting in less deleterious effects to patients with cancer than pan-HDAC inhibitors Figure 6.…”

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

“…16 Indeed, the proliferation defect in embryonic stem cells is rescued by deleting P21. 79 Deleting both Hdac1 and Hdac2 in dividing cells results in a similar cell cycle block in G1 phase. 39 Fibroblasts lacking both HDAC1 and HDAC2 fail to proliferate in culture and exhibit a strong cell cycle block in the G1 phase that is associated with upregulation of the CDK inhibitors p21 Cip1/Waf1 and p57 Kip2 .…”