HDAC1 (histone deacetylase 1)
2017-08-01 Emanuely Silva Chrun , Filipe Modolo , Filipe Ivan Daniel AffiliationFederal University of Santa Catarina, Florianopolis, Santa Catarina, [email protected] (ESC), Pathology Department, Federal University of Santa Catarina, Florianopolis, SC, Brazil. [email protected]; [email protected] (FM, FID)
Abstract
HDAC1 is a Class I histone deacetylase (HDACs) encoded by this gene. HDACs remove acetyl group from amino-terminal tail of histone lysine recovering the positive charge of histone tail, permitting interactions between negatively charged DNA and histone protein, resulting in chromatin structure condensation which is associated with gene repression. Overexpression of this protein has been related to several malignancies, controlling tumour suppressor genes expression, feasible prognostics factor, and medications target. This paper propound data about HDAC1 gene, its protein encoded and function.
DNA/RNA
Description
Located in chromosome 1. The entire HDAC1 gene is approximately 41,550 bases (start: 32,292,086 and end: 32,333,635 bp; orientation: Plus strand) and contains 14 exons.
Proteins
Expression
Ubiquitously.
Localisation
HDAC1 is found mainly in the nucleus.
Function
HDAC1 is an enzyme responsible for epigenetic alterations leading to modulation of chromatin structure and transcriptional regulation across lysine residues deacetylation on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (Fig. 1). It shows a role in cell cycle regulation and haematopoiesis (Dovey, et al. 2010). Deacetylation of TP53 by HDAC1 is a mechanism that participate of physiological activity of TP53 (Juan, et al. 2000 2000). It was also observed an important participation in cellular proliferation through direct regulation of CDKN1A (p21) gene (Zupkovitz, et al. 2010) 2010. HDAC2 is a HDAC1 homologue that, in part, compensates its loss and has redundant functions (Zupkovitz, et al. 2006 2006). These enzymes act through multiprotein co-repressor complexes such as: SIN3, NuRD, RCOR1 (CoREST) (Kelly and Cowley 2013).
Fig. 1. Chromatin remodeling by histone acetylation changes. HATs catalyse the addition of acetyl groups turning histone tail charge to negative, leading to chromatin opening, while HDACs remove acetyl group from amino-terminal tail of histone lysine recovering its positive charge, closing the chromatin structure.
Homology
HDAC1 shares high homology between diverse species (Table 1).
Table 1. Comparative identity of human HDAC1 and its homologs in other species).
Table 1. Comparative identity of human HDAC1 and its homologs in other species).
Gene | Identity | ||
| H. sapiens vs. | Symbol | Protein | DNA |
| P. troglogytes | HDAC1 | 99.8 | 99.4 |
| P. troglogytes | HDAC1 | 99.6 | 99.4 |
| M. mulata | LOC708441 | 99.8 | 97.8 |
| C. lupus | HDAC1 | 99.2 | 94.1 |
| B. taurus | HDAC1 | 99.2 | 93.9 |
| M. musculus | Hdac1 | 99.4 | 90.5 |
| R. norvegicus | Hdac1 | 99.2 | 90.9 |
| G. gallus | Hdac1 | 93.3 | 79.2 |
| D. melanogaster | Rpd3 | 82.1 | 72.2 |
| A. gambiae | AgaP_AGAP006511 | 83.1 | 72.8 |
| C. elegans | hda-3 | 69.5 | 63.5 |
| S. cerevisiae | RPD3 | 64.8 | 60.3 |
| K. lactis | KLLA0E01981g | 65.4 | 61.2 |
| E. gossypii | AGOS_AGR395W | 65.0 | 62.2 |
| S. pombe | clr6 | 64.5 | 63.2 |
| M. oryzae | MGG_05857 | 66.7 | 63.9 |
| N. crassa | NCU00824 | 66.1 | 62.8 |
| A. thaliana | HD1 | 67.6 | 63.4 |
| O. sativa | Os02g02124900 | 68.3 | 64.0 |
| O. sativa | Os06g0583400 | 69.2 | 65.4 |
Mutations
Note
A total of 60 substitution missense, 5 substitution nonsense, 29 substitution synonymous, no insertion frameshift, no deletions inframe, 2 deletion frameshift, none complex and none other mutations are reported in COSMIC (Catalogue of somatic mutations in cancer); it was found 110 mutated samples from a total of 29924 tested samples.
Implicated in
Entity name
Oral squamous cell carcinoma
Note
HDAC1 overexpression was found in 55.10% of 49 mobile tongue squamous cell carcinoma evaluated whereas most of the cells from non-neoplastic epithelium presents negative immunoexpression for HDAC1 (Theocharis, et al. 2011). HDAC1 was overexpressed in 70% of lip squamous cell carcinoma (Fig.2) and in 77% of actinic cheilitis, with immunoexpression increasing in preneoplastic cases with severe epithelial dysplasia, and in neoplastic cases with poor differentiation (Chrun, et al. 2017).
Fig. 2. Immunoexpression of HDAC1 in lip squamous cell carcinoma.
Entity name
Esophageal cancer
Note
Comparing H4 acetylation and HDAC1 expression, it was observed hyperacetylation of H4 and decreased HDAC1 expression from esophageal normal tissue through esophageal carcinoma, suggesting that the equilibrium between HDAC and HAT is interrupted in this carcinoma (Toh, et al. 2003). Few cases of esophageal cancer were reported with HDAC1 overexpression when compared to normal esophageal mucosa (15%) (Nakagawa, et al. 2007). Esophageal adenocarcinoma also presented subexpression in majority of cases and was not associated to prognostic factor (Langer, et al. 2010).
Entity name
Thyroid cancer
Note
HDAC1 immunoexpression was found in 99% of 47 thyroid malignances (papillary, follicular, medullary, and anaplastic thyroid carcinomas) and 23 benign thyroid tumors, with significant relation to tumor size, without difference in expression between malignant and benign thyroid tumors (Giaginis, et al. 2014). Nakagawa and collaborators reported immunoreactivity in all evaluated cases of papillary thyroid tumors (Nakagawa, et al. 2007).
Entity name
Gastric cancer
Note
HDAC1 overexpression was detected by semi-quantitative RT-PCR, immunoblot analysis, and immunohistochemistry in gastric cancer tissues compared to its corresponding normal tissue (Choi, et al. 2001; Nakagawa, et al. 2007). Sudo and colleagues found association between HDAC expression and aggressive behavior of primary gastric cancer. In this study, HDAC1 overexpression was found by quantitative reverse transcription-PCR in gastric cancer tissue in 77% of the cases, with higher expression correlated to lymph vessel and vascular vessel permeations, advanced stage of the disease, and lymph node metastasis (Sudo, et al. 2011).
Entity name
Colorectal cancer
Note
When comparing colorectal carcinoma cells and normal colonic mucosa by reverse transcription (RT)-PCR (Ishihama, et al. 2007) and immunohistochemistry (Nakagawa, et al. 2007) there was a greater HDAC1 expression in cancer than in normal colonic epithelium. Bernard and collaborators evaluated tissue microarray (TMA) with 254 colorectal adenocarcinomas samples and 50 normal colorectal tissues, showing no significant difference between normal and cancerous tissues, but suggested combination of higher HDAC expression and clinical outcomes for these patients (Benard, et al. 2015).
Entity name
Pancreatic cancer
Note
HDAC1 with HDAC2 and SIN3A were recognized as complex silencing regulators of CDH1 (E-cadherin), thus involved in pancreatic adenocarcinoma metastasis (von Burstin, et al. 2009; Aghdassi, et al. 2012). Several HDACs were evaluated in (pNET): higher expression of HDAC1 was observed in high grade pNET and its expression showed positive correlation with mitotic (pHH3) and proliferation (Ki-67) index (Klieser, et al. 2017).
Entity name
Lymphomas
Note
Hodgkin`s lymphoma exhibited higher immunoexpression of HDAC1 when analysing 283 TMA (Adams, et al. 2010). In diffuse large B-cell lymphomas (DLBCL) HDAC1 immunoexpression was higher in comparison to reactive lymphoid hyperplasia which was correlated to cell proliferation index (Ki67) in the development of DLBCL, and associated with aggressiveness/poor survival of DLBCL patients (Min, et al. 2012). On the other hand, Lee and colleagues found faintly nuclear staining in few cases of 91 DLBCL samples submitted to immunohistochemistry (Lee, et al. 2014).
Entity name
Leukemias
Note
Moreno and collaborators evaluated 94 cases of childhood acute lymphoblastic leukaemia (ALL) and found HDAC1 mRNA increased expression in T-cell ALL when compared to B-cell ALL. Yang et al. also found higher HDAC1 mRNA in ALL. (Moreno, et al. 2010). Quantitative real-time polymerase chain reaction also revealed higher HDAC1 expression in ALL (Yang, et al. 2015). Clinicopathological parameters indicated that overexpression of HDAC1 may be related to unfavourable prognosis of childhood ALL (Gruhn, et al. 2013).
Entity name
Lung cancer
Note
HDAC1 is highly expressed in lung cancer (Nakagawa, et al. 2007). A correlation between HDAC1 mRNA and protein levels showed that HDAC1 gene expression might be involved with lung cancer progression (Sasaki, et al. 2004).
Entity name
Prostate cancer
Note
Up-regulation of HDAC1 in prostate cancer compared to benign prostatic hyperplasia was demonstrated by immunohistochemistry (Patra, et al. 2001; Nakagawa, et al. 2007). Weichert and collaborators achieved immunohistochemistry for Class I HDAC isoforms in prostate carcinomas, showing HDAC1, HDAC2 and HDAC3 stronger expression accompanied by tumor cell proliferation raising (Weichert, et al. 2008). Overexpression of HDAC1 was also related to major increase of hormone refractory in prostate cancer and augmentation of proliferation (Halkidou, et al. 2004).
Entity name
Breast cancer
Note
HDAC1 was evaluated in TMA from 238 patients with primary breast cancer and presented wide variation in positive imunnoexpression (Muller, et al. 2013). While Nakagawa (Nakagawa, et al. 2007) and Ververis (Ververis and Karagiannis 2012) showed higher expression of HDAC1 by immunohistochemistry and immunofluorescence respectively. Suzuki and colleagues detected a decrease in its expression from normal tissue through invasive ductal carcinoma, and from high grade through intermediate/low grade carcinoma (Suzuki, et al. 2009). Higher expression of HDAC1 was related to molecular subtypes (Luminal A, Luminal B, HER overexpressed, and triple-negative) and with improved overall survival (Seo, et al. 2014).
Entity name
Ovarian cancer
Note
HDAC1 immunoexpression showed positive correlation with Ki-67 and inverse correlation with E-cadherin in 115 cases of ovarian tumors, suggesting an important participation of HDAC1 in cellular proliferation. Its overexpression was also associated with poor outcome (Hayashi, et al. 2010). Immunoreactivity for HDAC1 was sighted in 95% of cases evaluated, but without significant difference between histological subtypes of ovarian cancer (Nakagawa, et al. 2007). By immunohistochemistry and qRT-PCR, HDAC1 and DNMT3B revealed positive correlation in ovarian cancer; HDAC1 was highly expressed in comparison to normal ovarian tissue (Gu, et al. 2013). In a population-based cohort of 465 ovarian carcinomas, Weichert and collaborators observed higher level expression of HDAC1 and positive correlation with Ki67, indicating its participation in cell proliferation without significant interference in prognostic (Weichert 2009).
Entity name
Endometrial cancer
Note
Strong HDAC1 immunoexpression was observed in endometrial stromal sarcoma, and it was suggested that this expression is linked to lower than 10 years disease free survival (Baek, et al. 2016). Endometrial adenocarcinomas compared to normal endometrium exhibited reduction in HDAC1 expression (Krusche, et al. 2005). However, in other research, endometrial carcinomas presented higher HDAC1 expression in comparison to normal endometrial tissue (Fakhry, et al. 2010). Weichert and colleagues evaluated 149 endometrial carcinomas and showed a higher level of HDAC1 expression that was positively correlated with cell proliferation indicator (Ki-67) and associated to 10 years survival decrease (Weichert 2009).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 20415600 | 2010 | Class I histone deacetylases 1, 2 and 3 are highly expressed in classical Hodgkin's lymphoma. | Adams H et al |
| 22147512 | 2012 | Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. | Aghdassi A et al |
| 27127168 | 2016 | Immunohistochemical Characterization of Histone Deacetylase as a Potential Prognostic Marker and Therapeutic Target in Endometrial Stromal Sarcoma. | Baek MH et al |
| 25307864 | 2015 | Nuclear expression of histone deacetylases and their histone modifications predicts clinical outcome in colorectal cancer. | Benard A et al |
| 11749695 | 2001 | Expression profile of histone deacetylase 1 in gastric cancer tissues. | Choi JH et al |
| 28107582 | 2017 | Immunoexpression of HDAC1, HDAC2, and HAT1 in actinic cheilitis and lip squamous cell carcinoma. | Chrun ES et al |
| 20404188 | 2010 | Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. | Dovey OM et al |
| 20178884 | 2010 | Immunohistochemical detection of histone deacetylases in endometrial carcinoma: involvement of histone deacetylase 2 in the proliferation of endometrial carcinoma cells. | Fakhry H et al |
| 23873102 | 2014 | Clinical significance of histone deacetylase (HDAC)-1, HDAC-2, HDAC-4, and HDAC-6 expression in human malignant and benign thyroid lesions. | Giaginis C et al |
| 23948281 | 2013 | The expression of histone deacetylase 4 is associated with prednisone poor-response in childhood acute lymphoblastic leukemia. | Gruhn B et al |
| 23420051 | 2013 | Investigation of the expression patterns and correlation of DNA methyltransferases and class I histone deacetylases in ovarian cancer tissues. | Gu Y et al |
| 15042618 | 2004 | Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. | Halkidou K et al |
| 20049841 | 2010 | Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin. | Hayashi A et al |
| 17720775 | 2007 | Expression of HDAC1 and CBP/p300 in human colorectal carcinomas. | Ishihama K et al |
| 10777477 | 2000 | Histone deacetylases specifically down-regulate p53-dependent gene activation. | Juan LJ et al |
| 23697933 | 2013 | The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. | Kelly RD et al |
| 15770522 | 2005 | Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. | Krusche CA et al |
| 20924032 | 2010 | Expression of class I histone deacetylases (HDAC1 and HDAC2) in oesophageal adenocarcinomas: an immunohistochemical study. | Langer R et al |
| 25076845 | 2014 | Expression of histone deacetylases in diffuse large B-cell lymphoma and its clinical significance. | Lee SH et al |
| 23627572 | 2013 | Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer--overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. | Müller BM et al |
| 23109994 | 2012 | Expression of HAT1 and HDAC1, 2, 3 in Diffuse Large B-Cell Lymphomas, Peripheral T-Cell Lymphomas, and NK/T-Cell Lymphomas. | Min SK et al |
| 20636436 | 2010 | Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. | Moreno DA et al |
| 17786334 | 2007 | Expression profile of class I histone deacetylases in human cancer tissues. | Nakagawa M et al |
| 11563853 | 2001 | Histone deacetylase and DNA methyltransferase in human prostate cancer. | Patra SK et al |
| 15474665 | 2004 | Histone deacetylase 1 mRNA expression in lung cancer. | Sasaki H et al |
| 25548579 | 2014 | Expression of Histone Deacetylases HDAC1, HDAC2, HDAC3, and HDAC6 in Invasive Ductal Carcinomas of the Breast. | Seo J et al |
| 21725604 | 2011 | Histone deacetylase 1 expression in gastric cancer. | Sudo T et al |
| 19383825 | 2009 | Protein acetylation and histone deacetylase expression associated with malignant breast cancer progression. | Suzuki J et al |
| 21457345 | 2011 | Histone deacetylase-1 and -2 expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. | Theocharis S et al |
| 12579268 | 2003 | Histone H4 acetylation and histone deacetylase 1 expression in esophageal squamous cell carcinoma. | Toh Y et al |
| 22347520 | 2012 | An atlas of histone deacetylase expression in breast cancer: fluorescence methodology for comparative semi-quantitative analysis. | Ververis K et al |
| 19103471 | 2009 | HDAC expression and clinical prognosis in human malignancies. | Weichert W et al |
| 18212746 | 2008 | Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. | Weichert W et al |
| 25944469 | 2015 | Analysis of class I and II histone deacetylase gene expression in human leukemia. | Yang H et al |
| 16940178 | 2006 | Negative and positive regulation of gene expression by mouse histone deacetylase 1. | Zupkovitz G et al |
| 19362090 | 2009 | E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. | von Burstin J et al |
Other Information
Locus ID:
NCBI: 3065
MIM: 601241
HGNC: 4852
Ensembl: ENSG00000116478
Variants:
dbSNP: 3065
ClinVar: 3065
TCGA: ENSG00000116478
COSMIC: HDAC1
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000116478 | ENST00000373548 | Q13547 |
| ENSG00000116478 | ENST00000373548 | Q6IT96 |
| ENSG00000116478 | ENST00000428704 | Q5TEE2 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA10832 | corticosteroids | Chemical | ClinicalAnnotation | associated | PD | 24307847 | |
| PA443450 | Asthma | Disease | ClinicalAnnotation | associated | PD | 24307847 | |
| PA451846 | valproic acid | Chemical | Pathway | associated | 23407051 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38254102 | 2024 | HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling. | 0 |
| 38329647 | 2024 | ZNF787 and HDAC1 Mediate Blood-Brain Barrier Permeability in an In Vitro Model of Alzheimer's Disease Microenvironment. | 0 |
| 38505872 | 2024 | HDAC1-Mediated Downregulation of NEU1 Exacerbates the Aggressiveness of Cervical Cancer. | 0 |
| 38812060 | 2024 | Unveiling the role of HP1α-HDAC1-STAT1 axis as a therapeutic target for HP1α-positive intrahepatic cholangiocarcinoma. | 1 |
| 38254102 | 2024 | HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling. | 0 |
| 38329647 | 2024 | ZNF787 and HDAC1 Mediate Blood-Brain Barrier Permeability in an In Vitro Model of Alzheimer's Disease Microenvironment. | 0 |
| 38505872 | 2024 | HDAC1-Mediated Downregulation of NEU1 Exacerbates the Aggressiveness of Cervical Cancer. | 0 |
| 38812060 | 2024 | Unveiling the role of HP1α-HDAC1-STAT1 axis as a therapeutic target for HP1α-positive intrahepatic cholangiocarcinoma. | 1 |
| 36287107 | 2023 | HDAC1 regulates the chromatin landscape to control transcriptional dependencies in chronic lymphocytic leukemia. | 3 |
| 36346011 | 2023 | Regulation of osteogenesis in bone marrow-derived mesenchymal stem cells via histone deacetylase 1 and 2 co-cultured with human gingival fibroblasts and periodontal ligament cells. | 4 |
| 36587730 | 2023 | Proteomics-based trapping with single or multiple inactive mutants reproducibly profiles histone deacetylase 1 substrates. | 0 |
| 37121053 | 2023 | HDAC1 mediates epithelial-mesenchymal transition and promotes cancer cell invasion in glioblastoma. | 3 |
| 37661113 | 2023 | Evaluation of epigenetic-related gene expression (DNMT, HDAC1) in Iranian patients with systemic lupus erythematosus. | 0 |
| 37737560 | 2023 | BCL11B and the NuRD complex cooperatively guard T-cell fate and inhibit OPA1-mediated mitochondrial fusion in T cells. | 1 |
| 37878419 | 2023 | GSE1 links the HDAC1/CoREST co-repressor complex to DNA damage. | 0 |
Citation
Emanuely Silva Chrun ; Filipe Modolo ; Filipe Ivan Daniel
HDAC1 (histone deacetylase 1)
Atlas Genet Cytogenet Oncol Haematol. 2017-08-01
Online version: http://atlasgeneticsoncology.org/gene/40802/hdac1-(histone-deacetylase-1)
