Skip to main content
NCBI home page
Cell Cycle logoLink to Cell Cycle
. 2011 Feb 1;10(3):406–412. doi: 10.4161/cc.10.3.14712

Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis

Jennifer Jurkin 1,†,#, Gordin Zupkovitz 1,#, Sabine Lagger 1,#, Reinhard Grausenburger 1,‡,#, Astrid Hagelkruys 1, Lukas Kenner 2, Christian Seiser 1,✉
PMCID: PMC3115015  PMID: 21270520

Abstract

Histone deacetylases (HDACs) are negative regulators of gene expression and have been implicated in tumorigenesis and tumor progression. Therefore, HDACs are promising targets for antitumor drugs. However, the relevant isoforms of the 18 members encompassing HDAC family have not been identified. Studies utilizing either gene targeting or knockdown approaches reveal both specific and redundant functions of the closely related class I deacetylases HDAC1 and HDAC2 in the control of proliferation and differentiation. Combined ablation of HDAC1 and HDAC2 in different cell types led to a severe proliferation defects or enhanced apoptosis supporting the idea that both enzymes are relevant targets for tumor therapy. In a recent study on the role of HDAC1 in teratoma formation we have reported a novel and surprising function of HDAC1 in tumorigenesis. In this tumor model HDAC1 attenuates proliferation during teratoma formation. In the present work we discuss new findings on redundant and unique functions of HDAC1 and HDAC2 as regulators of proliferation and tumorigenesis and potential implications for applications of HDAC inhibitors as therapeutic drugs.

Key words: tumor therapy, HDAC inhibitor, teratoma, chromatin, epigenetics, proliferation, histone acetylation, tumorigenesis

The Class I Deacetylases HDAC1 and HDAC2

Histone deacetylases are enzymes catalyzing the removal of acetyl moieties from lysine residues. Originally identified as histone deacetylating enzymes and regulators of chromatin structure, a growing number of non-histone substrates whose activities are regulated by reversible acetylation has been identified.1,2 Consequently, essential functions of histone deacetylases have been found in various biological processes, including proliferation and cell survival. Most importantly, increased levels of histone deacetylases were found in various cancers3 and inhibition of HDAC activity led to decreased proliferation and enhanced apoptosis in neoplastic transformed but not in normal cells.4

In mammals, 18 different histone deacetylases have been identified and grouped according to their homology to yeast deacetylases into four classes.5 The class I enzymes HDAC1 and HDAC2 are ubiquitously expressed and found to be overexpressed in several tumor types and are therefore promising targets for HDAC inhibitor mediated tumor therapy.6

The genes for HDAC1 and HDAC2 originate from a gene duplication7,8 and the corresponding mouse and human proteins are highly homologous (86% identity on the amino acid level). Like all deacetylases, HDAC1 and HDAC2 lack a DNA binding domain and are therefore recruited by transcription factors either as homo- or heterodimers or as part of multifactor repressor complexes.8

During the last years, important insights about the functional impact of HDAC1 and HDAC2 on the regulation of proliferation, apoptosis and tumorigenesis came from loss-of-function studies in mice. One common theme of several HDAC1/HDAC2 knockdown and knockout studies is redundancy and compensation. In a number of reports, increased levels of HDAC2 have been observed upon inactivation of HDAC1 or, vice versa, HDAC1 was upregulated upon deletion of HDAC2.9–12 In fact, we have detected increased HDAC2 expression in all cell systems, in which HDAC1 was ablated.9,13,14 As shown in Figure 1, loss of HDAC1 in embryonic stem (ES) cells, immortalized fibroblasts and F9 embryonal carcinoma cells leads to upregulation of HDAC2 protein. This increase is reversible, since re-introduction of HDAC1 into HDAC1 knockout (KO) ES cells results again in reduced HDAC2 levels (Fig. 1A). The change in HDAC2 protein is not only reversible but also dose-dependent, since expression of different amounts of HDAC1 in HDAC1 KO fibroblasts results in a corresponding reduction in HDAC2 levels (Fig. 1B). Finally, we observed a compensatory mechanism for both HDAC1 and HDAC2 in F9 cells: shRNA-mediated knockdown of HDAC1 led to upregulation of HDAC2 protein, while ablation of HDAC2 resulted in increased levels of HDAC1 (Fig. 1C). These results are in agreement with other published mouse knockout studies.12,15

Figure 1.

Figure 1

Open in a new tab

Crosstalk between HDAC1 and HDAC2. (A–C) Interdependent expression of HDAC1 and HDAC2 in different mouse cell types. Protein levels of HDAC1 and HDAC2 in whole cell extracts were analyzed on immunoblots with β-actin as loading control. (A) Analysis of vector-infected wild-type ES cells (WTvec), vector-infected HDAC1-deficient ES cells (HD1 KOvec) and HDAC1-deficient ES cells with re-introduced HDAC1 (HD1 KOreA and HD1 KOreB) (review in ref. 19). (B) Analysis of immortalized vector-infected wild-type fibroblasts (WTvec) and vector-infected HDAC1-deficient fibroblasts (review in ref. 8), or HDAC1-deficient fibroblasts expressing different amounts of HDAC1 protein upon infection with a retroviral HDAC1 encoding pBABE-puro vector (HD1 KOreA, B and C) (upper part). HDAC1 and HDAC2 protein levels were quantified by densitometric scanning and shown relative to the values of β-actin (lower part). (C) Analysis of F9 embryonal carcinoma cells infected with lentiviral vectors encoding a control shRNA (NT), an HDAC1 targeting shRNA (HD1 KD) or an HDAC2 targeting shRNA (HD2 KD) (review in ref. 14). (D) HDAC2 upregulation in the absence of HDAC1 is not caused by increased mRNA levels. Analysis of HDAC1 and HDAC2 mRNA expression by qRT PCR in wild-type and HDAC1-deficient ES cells (upper part), wild-type and HDAC1-deficient fibroblasts (middle part) and wild-type, HDAC1 knockdown or HDAC2 knockdown F9 cells. HDAC1 and HDAC2 mRNA expression is shown relative to the control GAPDH.

The co-repressor HDAC1 was previously shown to negatively regulate transcription of its own gene in an autoregulatory feedback loop.16 Therefore, it was tempting to speculate that the crosstalk between HDAC1 and HDAC2 takes place on the level of transcriptional regulation. However, quantitative Realtime (qRT) analysis of HDAC1 and HDAC2 mRNA levels revealed that the 2.0–2.5-fold increase in HDAC2 protein levels (as determined by densitometric scanning of the immunoblots) upon HDAC1 ablation in the three different cell types is not accompanied by a significant increase in the corresponding transcript levels (Fig. 1D). These results, which are in accordance with another recent report on HDAC1 KO ES cells,17 suggest a translational or post-translational regulatory mechanism controlling the crosstalk between HDAC1 and HDAC2. Taken together these data demonstrate that the expression of the class I deacetylases HDAC1 and HDAC2 are tightly coupled to each other.

HDAC1 and HDAC2 as Regulators of Proliferation and Tumor Development

In agreement with the antiproliferative effects of HDAC inhibitors, knockout studies in mice and knockdown studies in human tumor cells have revealed individual and overlapping regulatory functions of HDAC1 and HDAC2 for proliferation, cell survival and differentiation. In the following section we discuss these functions in more detail.

Specific functions of HDAC1.

Mouse HDAC1 was originally identified as growth factor regulated gene with high expression in proliferating and transformed cells.18 Targeted deletion of HDAC1 in mice results in an early embryonic lethal phenotype due to severe developmental problems.9 In this setting, loss of HDAC1 during embryogenesis cannot be compensated by HDAC2 suggesting either a specific function of HDAC1 or differences in the expression profiles of the two enzymes during early embryogenesis. HDAC1-deficient embryos and ES cells are characterized by an overall reduced cellular proliferation rate caused by increased levels of the cyclin dependent kinase (CDK) inhibitor p21 and p27.9 Similarly, in mouse embryonic fibroblasts, deletion of HDAC1, but not of HDAC2, caused a partial G1 arrest, which was further reinforced by additional deletion of HDAC2.12,19 In T lymphocytes, HDAC1 was found to be involved in the restriction of cytokine expression and proliferation.13 In tumorigenic cells, knockdown of HDAC1, but not HDAC2, affected the growth of human osteosarcoma and breast cancer cells.10 Knockdown of HDAC1 also resulted in reduced proliferation rates of HeLaS3 cells20 and induction of autophagy.21

Specific functions of HDAC2.

In general HDAC2 seems to have a rather specific anti-apoptotic function in cancer cells. For instance, knockdown of HDAC2 in cancer cells resulted in a more differentiated phenotype and increased apoptosis caused by augmented levels of p21.22 Moreover, HDAC2 knockdown in breast cancer cells induced the binding activity of p53, hence leading to inhibition of proliferation and cellular senescence.23 Selective inhibition of HDAC2, but not HDAC1, increased the sensitivity of breast cancer cells to tamoxifen treatment by aborting the expression of estrogen und progesterone receptors.24 Similarly, depletion of HDAC2, but not HDAC1 or HDAC6, was shown to increase the sensitivity of breast cancer cells to topoisomerase inhibitor induced apoptosis.25 Moreover, HDAC2 KO mice displayed decreased tumor rates when crossed into APC (min) mice.11 In agreement with an anti-apoptotic function of HDAC2, it was recently shown that HDAC2, but not HDAC1, conferred therapeutic resistance towards the topoisomerase II inhibitor etoposide in PDAC cells by negative regulation of the pro-apoptotic BH3-only protein NOXA.26

Similar functions of HDAC1 and HDAC2.

Similar effects of inactivation of either HDAC1 or HDAC2 were found in ovarian cancer cells, in which deletion of either HDAC1 or HDAC2 led to a minor decrease in proliferation.27 Moreover, knockdown of either HDAC1 or HDAC2 resulted in the sensitization of CLL cells for Trail induced apoptosis.28 Proliferation of colon cancer cells was reduced by knockdown of either HDAC1 or HDAC2.29

Redundant functions of HDAC1 and HDAC2.

With few exceptions mentioned above targeted deletion of either HDAC1 or HDAC2 has caused no overt phenotype in most tissues or cell types. Thus, inactivation of either one of the two class I HDACs in the heart,30 glial cells,31 neurons32 or B cells12 did not result in any obvious defects in these lineages. Importantly, combined knockout of HDAC1 and HDAC2 led to dramatic effects on proliferation, differentiation or cell survival indicating redundant functions of HDAC1 and HDAC2 in these cell types. For instance, simultaneous ablation of HDAC1 and HDAC2 in fibroblasts led to a strong cell cycle block in the G1 phase accompanied by upregulation of the CDK inhibitors p21 and p57.12 Another report shows that the senescence-like G1 cell cycle arrest in HDAC1/HDAC2-deficient fibroblasts does not depend on the p53/p21 pathway.15 With regard to transformed or tumorigenic cells, combined but not individual ablation of HDAC1 and HDAC2 in SV40LT-antigen immortalized and H-Ras V12 transformed fibroblasts resulted in cell death.33

In contrast, simultaneous deletion of HDAC1 and HDAC2 in non-proliferating cells such as resting fibroblasts, postmitotic cardiac cells or non-dividing hepatocytes and B cells has no obvious consequences.12,15,33 All these finding on redundant and non-redundant functions of HDAC1 and HDAC2 suggest that these deacetylases are positive regulators of proliferation and thus valuable targets for tumor drugs.

HDAC1 as Negative Regulator of Cell Proliferation

Very recently, an unexpected function of HDAC1 in tumorigenesis and proliferation control was discovered.14 Using an experimental teratoma system we have analyzed tumors that are derived from either wildtype or HDAC1 KO ES cells. HDAC1-deficient teratomas were similar in size but showed induced proliferation and apoptosis, when compared to wildtype tumors and resembled more malignant teratocarcinomas. In particular epithelial structures displayed reduced differentiation and increased proliferation and showed some features of epithelial to mesenchymal transition (EMT) such as strong expression of SNAIL1 and delocalized cytosolic staining of E-cadherin. SNAIL1, a regulator of epithelial cell plasticity, was found to be negatively regulated by HDAC1 and became upregulated upon HDAC1 knockdown in F9 embryonal carcinoma cells. During EMT, SNAIL1 negatively regulates E-cadherin expression via the co-repressor HDAC1. HDAC2, which is upregulated in HDAC1-deficient teratomas cannot compensate for the loss of HDAC1 at the E-cadherin promoter. Thus, HDAC1-deficient embryonal carcinoma cells express positively regulated SNAIL1 targets such as the metastatic factors MMP9 and ZEB1 but also at the same time SNAIL1 repressed genes such as E-cadherin. The simultaneous activation of proliferation-driving and differentiation-specific genes causes conflicting signals, which might be in part responsible for the increase in apoptosis observed in HDAC1 KO teratomas. However, in cells, in which the positive SNAIL1 targets dominate, the balance is shifted towards proliferation. The crucial function of SNAIL1 in this tumor system is underlined by the fact that SNAIL1 knockdown teratomas show dramatically reduced proliferation.

It is plausible that also in other signaling pathways general chromatin modifiers such as HDAC1 and HDAC2 could act at different levels of the same pathway. For instance, both enzymes are involved in the repression of the CDK inhibitor p21. Loss or inhibition of HDAC1/HDAC2 should therefore result in hypophosphorylation of the retinoblastoma (RB) protein and repression of E2F target genes. However, HDAC1 is at the same time an RB-associated co-repressor that is involved in negative regulation of some E2F target genes.34 The biological consequence of HDAC1 inhibition in this scenario will be most probably affected by the cell type specific importance of E2F-dependent and independent p21 targets.

An important finding of the HDAC1 teratoma study was the fact, that the phenotype of HDAC1 KO teratomas is mirrored in human teratoma samples. More differentiated mature teratomas showed high levels of HDAC1 and low levels of HDAC2, whereas aggressive, less differentiated teratocarcinomas displayed low levels of HDAC1 but high expression of HDAC2 and SNAIL1. Thus, HDAC1 and HDAC2 could represent valuable prognostic markers for teratocarcinoma classification in the future.

In general, the effect of HDAC1/HDAC2 and other ubiquitously expressed deacetylases might depend on the function of cell type specific target genes. For instance, we have recently shown that ablation of HDAC1 in T lymphocytes results in upregulation of specific cytokines and enhanced proliferation of peripheral T cells.13 These novel findings are surprising and have potential impact on the development of HDAC inhibitors.

HDAC1 and HDAC2 as Targets of HDAC Inhibitors

Several HDAC inhibitors are currently tested in clinical trials and two compounds (Vorinostat and Romidepsin) have been FDA approved for the treatment of cutaneous T-cell lymphoma. Side effects such as fatigue, diarrhea and thrombocytopenia have been described as consequence of HDAC inhibitor treatment in clinical trials.35 Therefore, considerable efforts have been made during the last years to develop more specific or even isoform-specific HDAC inhibitors.

In order to investigate the effect of HDAC inhibitors in the absence of either HDAC1 or HDAC2, we have analyzed the impact of the general HDAC inhibitor trichostatin A (TSA) and the more specific inhibitors valproic acid and MS-275 on HDAC1- and HDAC2-deficient embryonal carcinoma cells. The benzamide MS-275 preferentially inhibits the class I enzymes HDAC1, HDAC2 and HDAC3 with a certain preference for HDAC1 (reviewed in ref. 6) and the antiepileptic drug valproic acid (VPA) induces the proteosomal degradation of HDAC2 and inhibits class I HDACs.36 The effect of HDAC inhibitors on histone acetylation on wildtype F9 cells, F9 HDAC1 knockdown cells and F9 HDAC2 knockdown cells was tested for acetylation of lysine 56 at histone H3 (H3K56ac) and general histone H4 acetylation. The H3K56ac mark has been recently identified as substrate for HDAC1.17 All three inhibitors strongly induced hyperacetylation of H3K56 and histone H4 in the presence and absence of HDAC1 or HDAC2 (Fig. 2A). This result is in contrast to a previous report showing that HDAC2-deficient human cancer cells do not respond to the general HDAC inhibitor TSA.37 Taken together F9 embryonal carcinoma cells are still sensitive to general and class I specific HDAC inhibitors in the absence of either HDAC1 or HDAC2. These data suggest that loss of a single class I deacetylase has no strong impact on the responsiveness of these cells towards HDAC inhibitors.

Figure 2.

Figure 2

Open in a new tab

Effect of HDAC inhibitors on histone acetylation and p21 expression in F9 cells in the presence or absence of HDAC1 or HDAC2. Histones and total RNA were isolated from F9 cells infected with lentiviral vectors encoding a control shRNA (NT), an HDAC1 targeting shRNA (HD1 KD) or an HDAC2 targeting shRNA (HD2 KD) (review in ref. 14) treated with vehicle or HDAC inhibitors as indicated. (A and B) Histone hyperacetylation is induced by HDAC inhibitors in the absence of either HDAC1 or HDAC2. Histones were extracted and analyzed on immunoblots with antibodies specific for histone H3 acetylated at K56 (H3K56ac), pan-acetylated histone H4 and the C-terminus of histone H3 (cH3) as loading control. (A) Cells were treated with vehicle DMSO, 66.1 nM trichostatin A (TSA), 10 mM valproic acid (VPA) or 2 µM MS-275 for 24 hours. (B) Cells were treated with vehicle DMSO or different concentrations of MS-275 for 24 hours. Lower part: Signals were quantified by densitometric scanning and are shown relative to the signals of cH3. The data represent two independent experiments. (C and D) p21 expression was analyzed by qRT PCR and is shown relative to the control GAPDH. (C) p21 expression in wild-type F9 cells or upon ablation of either HDAC1 or HDAC2 in the absence of HDAC inhibitors. (D) p21 expression in wild-type and HDAC1 or HDAC2 knockdown F9 cells treated with different concentrations of MS-275 for 24 hours.

Given a reported relative preference of MS-275 for HDAC1, we asked next whether loss of HDAC1 or HDAC2 affects the dose-dependent sensitivity of F9 cells towards this inhibitor. As read-out we used in addition to hyperacetylation of H3K56 and histone H4 the expression of the CDK inhibitor p21, one of the most reliable targets for HDAC inhibitors. Global acetylation of H3K56 and histone H4 did not significantly change in the absence of either HDAC1 or HDAC2 (data not shown). All three cell types, F9 control cells, HDAC1 knockdown cells and HDAC2 knockdown cells showed induced histone acetylation in response to increasing amounts of MS-275 (Fig. 2B). However, global hyperacetylation of H3K56 and histone H4 was less pronounced in the absence of either HDAC1 or HDAC2 confirming that both enzymes are relevant targets for MS-275. It is possible that the increased sensitivity of HDAC2 knockdown cells for H4 acetylation (0.02 µM MS-275) is due to higher HDAC1 levels in these cells.

As shown in Figure 2C, ablation of either HDAC1 or HDAC2 significantly induced the expression of p21 suggesting that both enzymes are involved in the repression of the CDK inhibitor in F9 cells. Surprisingly, induction of p21 expression by MS-275 was more pronounced in the absence of both HDAC1 and HDAC2 (Fig. 2D). This could be explained by a more open p21-associated chromatin that is more responsive to the HDAC inhibitor upon ablation of HDAC1 or HDAC2. Indeed, by chromatin immunoprecipitation assays we observed an increase in two active chromatin marks, namely H3K9 acetylation and H3K4 tri-methylation at the regulatory region of the p21 gene in both HDAC1 and HDAC2 knockdown cells (data not shown).

In summary, our results show that HDAC1 and HDAC2 have common (p21) and individual (SNAIL1, E-cadherin) targets in F9 cells (Fig. 2 and review in ref. 14). As expected these genes are also responsive to class I HDAC inhibitor MS-275. However, there is not always a strong correlation between the function of individual HDACs and the activity of more specific HDAC inhibitors. For instance, we have found only a relatively small overlap between HDAC1 target genes and MS-275 target genes in mouse ES cells (Gordin Zupkovitz and Christian Seiser, data unpublished). In this context, It is important to note that, as reviewed in reference 38, the selectivity profile of HDAC inhibitors is usually tested under conditions that do not reflect the in vivo situation. In a cellular context, HDAC1 and HDAC2 are often part of different multiprotein complexes and deacetylate besides different acetylated non-histone proteins a highly modified biopolymer, the chromatin.

Outlook

Given a potential role of HDAC1 as tumor suppressor, it will be important to test individual roles of HDAC1 and HDAC2 by loss-of-function studies in different cancer models. Analysis of the corresponding human tumor tissues will allow determining the prognostic value of the mouse models. Combined ablation of HDAC1 and HDAC2 severely affects the viability of all proliferating cell types tested until now. Therefore, the next step will be to analyze the effects of combined HDAC1/HDAC2 knockout in mouse tumor models. Depending on these results, it might be sufficient to develop HDAC inhibitors with specificity for HDAC1/HDAC2 without affecting other important class I deacetylases such as HDAC3. Finally, it will be crucial to validate specific HDAC inhibitors in mouse tumor models in comparison with the corresponding genetic deletions.

Acknowledgements

This work was supported by the Austrian Science Fund (FWF P18746-B12), the Herzfelder Family Foundation and the GEN-AU project “Epigenetic Plasticity of the Mammalian Genome” (Austrian Federal Ministry for Education, Science and Culture). Astrid Hagelkruys is a fellow of the International Ph.D., program ‘Molecular mechanism of Cell Signaling’ (Austrian Science Fund).

References

  • 1.Yang XJ, Seto E. Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol Cell. 2008;31:449–461. doi: 10.1016/j.molcel.2008.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Brandl A, Heinzel T, Kramer OH. Histone deacetylases: salesmen and customers in the post-translational modification market. Biology of the cell/under the auspices of the European Cell Biology Organization. 2009;101:193–205. doi: 10.1042/BC20080158. [DOI] [PubMed] [Google Scholar]
  • 3.Nakagawa M, Oda Y, Eguchi T, Aishima S, Yao T, Hosoi F, et al. Expression profile of class I histone deacetylases in human cancer tissues. Oncol Rep. 2007;18:769–774. [PubMed] [Google Scholar]
  • 4.Warrener R, Beamish H, Burgess A, Waterhouse NJ, Giles N, Fairlie D, et al. Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints. Faseb J. 2003;17:1550–1552. doi: 10.1096/fj.02-1003fje. [DOI] [PubMed] [Google Scholar]
  • 5.de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–749. doi: 10.1042/BJ20021321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bertrand P. Inside HDAC with HDAC inhibitors. European journal of medicinal chemistry. 2010;45:2095–2116. doi: 10.1016/j.ejmech.2010.02.030. [DOI] [PubMed] [Google Scholar]
  • 7.Khier H, Bartl S, Schuettengruber B, Seiser C. Molecular cloning and characterization of the mouse histone deacetylase 1 gene: integration of a retrovirus in 129SV mice. Biochim Biophys Acta. 1999;1489:365–373. doi: 10.1016/s0167-4781(99)00203-1. [DOI] [PubMed] [Google Scholar]
  • 8.Brunmeir R, Lagger S, Seiser C. Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. Int J Dev Biol. 2009;53:275–289. doi: 10.1387/ijdb.082649rb. [DOI] [PubMed] [Google Scholar]
  • 9.Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 2002;21:2672–2681. doi: 10.1093/emboj/21.11.2672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Senese S, Zaragoza K, Minardi S, Muradore I, Ronzoni S, Passafaro A, et al. Role for histone deacetylase 1 in human tumor cell proliferation. Mol Cell Biol. 2007;27:4784–4795. doi: 10.1128/MCB.00494-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Zimmermann S, Kiefer F, Prudenziati M, Spiller C, Hansen J, Floss T, et al. Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice. Cancer Res. 2007;67:9047–9054. doi: 10.1158/0008-5472.CAN-07-0312. [DOI] [PubMed] [Google Scholar]
  • 12.Yamaguchi T, Cubizolles F, Zhang Y, Reichert N, Kohler H, Seiser C, Matthias P. Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev. 2010;24:455–469. doi: 10.1101/gad.552310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Grausenburger R, Bilic I, Boucheron N, Zupkovitz G, El-Housseiny L, Tschismarov R, et al. Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J Immunol. 2010;185:3489–3497. doi: 10.4049/jimmunol.0903610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Lagger S, Meunier D, Mikula M, Brunmeir R, Schlederer M, Artaker M, et al. Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans. EMBO J. 2010;29:3992–4007. doi: 10.1038/emboj.2010.264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Wilting RH, Yanover E, Heideman MR, Jacobs H, Horner J, van der Torre J, et al. Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis. EMBO J. 2010;29:2586–2597. doi: 10.1038/emboj.2010.136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Schuettengruber B, Simboeck E, Khier H, Seiser C. Autoregulation of mouse histone deacetylase 1 expression. Mol Cell Biol. 2003;23:6993–7004. doi: 10.1128/MCB.23.19.6993-7004.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Dovey OM, Foster CT, Cowley SM. Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. Proc Natl Acad Sci USA. 2010;107:8242–8247. doi: 10.1073/pnas.1000478107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Bartl S, Taplick J, Lagger G, Khier H, Kuchler K, Seiser C. Identification of mouse histone deacetylase 1 as a growth factor-inducible gene. Mol Cell Biol. 1997;17:5033–5043. doi: 10.1128/mcb.17.9.5033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Zupkovitz G, Grausenburger R, Brunmeir R, Senese S, Tischler J, Jurkin J, et al. The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation. Mol Cell Biol. 30:1171–1181. doi: 10.1128/MCB.01500-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Glaser KB, Li J, Staver MJ, Wei RQ, Albert DH, Davidsen SK. Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Biochem Biophys Res Commun. 2003;310:529–536. doi: 10.1016/j.bbrc.2003.09.043. [DOI] [PubMed] [Google Scholar]
  • 21.Oh M, Choi IK, Kwon HJ. Inhibition of histone deacetylase1 induces autophagy. Biochem Biophys Res Commun. 2008;369:1179–1183. doi: 10.1016/j.bbrc.2008.03.019. [DOI] [PubMed] [Google Scholar]
  • 22.Huang BH, Laban M, Leung CH, Lee L, Lee CK, Salto-Tellez M, et al. Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ. 2005;12:395–404. doi: 10.1038/sj.cdd.4401567. [DOI] [PubMed] [Google Scholar]
  • 23.Harms KL, Chen X. Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res. 2007;67:3145–3152. doi: 10.1158/0008-5472.CAN-06-4397. [DOI] [PubMed] [Google Scholar]
  • 24.Bicaku E, Marchion DC, Schmitt ML, Munster PN. Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling. Cancer Res. 2008;68:1513–1519. doi: 10.1158/0008-5472.CAN-07-2822. [DOI] [PubMed] [Google Scholar]
  • 25.Marchion DC, Bicaku E, Turner JG, Schmitt ML, Morelli DR, Munster PN. HDAC2 regulates chromatin plasticity and enhances DNA vulnerability. Mol Cancer Ther. 2009;8:794–801. doi: 10.1158/1535-7163.MCT-08-0985. [DOI] [PubMed] [Google Scholar]
  • 26.Fritsche P, Seidler B, Schuler S, Schnieke A, Gottlicher M, Schmid RM, et al. HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA. Gut. 2009;58:1399–1409. doi: 10.1136/gut.2009.180711. [DOI] [PubMed] [Google Scholar]
  • 27.Khabele D, Son DS, Parl AK, Goldberg GL, Augenlicht LH, Mariadason JM, Rice VM. Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth: implications for therapy. Cancer Biol Ther. 2007;6:795–801. doi: 10.4161/cbt.6.5.4007. [DOI] [PubMed] [Google Scholar]
  • 28.Inoue S, Mai A, Dyer MJ, Cohen GM. Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res. 2006;66:6785–6792. doi: 10.1158/0008-5472.CAN-05-4563. [DOI] [PubMed] [Google Scholar]
  • 29.Weichert W, Roske A, Niesporek S, Noske A, Buckendahl AC, Dietel M, et al. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res. 2008;14:1669–1677. doi: 10.1158/1078-0432.CCR-07-0990. [DOI] [PubMed] [Google Scholar]
  • 30.Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 2007;21:1790–1802. doi: 10.1101/gad.1563807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ye F, Chen Y, Hoang T, Montgomery RL, Zhao XH, Bu H, et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nat Neurosci. 2009;12:829–838. doi: 10.1038/nn.2333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Montgomery RL, Hsieh J, Barbosa AC, Richardson JA, Olson EN. Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development. Proc Natl Acad Sci USA. 2009;106:7876–7881. doi: 10.1073/pnas.0902750106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Haberland M, Johnson A, Mokalled MH, Montgomery RL, Olson EN. Genetic dissection of histone deacetylase requirement in tumor cells. Proc Natl Acad Sci USA. 2009;106:7751–7755. doi: 10.1073/pnas.0903139106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature. 1998;391:601–605. doi: 10.1038/35410. [DOI] [PubMed] [Google Scholar]
  • 35.Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin Cancer Res. 2009;15:3958–3969. doi: 10.1158/1078-0432.CCR-08-2785. [DOI] [PubMed] [Google Scholar]
  • 36.Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003;22:3411–3420. doi: 10.1093/emboj/cdg315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ropero S, Fraga MF, Ballestar E, Hamelin R, Yamamoto H, Boix-Chornet M, et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nat Genet. 2006;38:566–569. doi: 10.1038/ng1773. [DOI] [PubMed] [Google Scholar]
  • 38.Mercurio C, Minucci S, Pelicci PG. Histone deacetylases and epigenetic therapies of hematological malignancies. Pharmacol Res. 2010;62:18–34. doi: 10.1016/j.phrs.2010.02.010. [DOI] [PubMed] [Google Scholar]

Articles from Cell Cycle are provided here courtesy of Taylor & Francis

RESOURCES