HDAC1 (histone deacetylase 1)

Description	HDAC1 protein consists of 482 amino acids with a molecular theoretical weight of 55.18 kDa. Human HDAC1 protein (GenBank Accession No. NM_004964), full length with C-terminal His-tag and C-terminal FLAG-tag, MW = 56 kDa, expressed in baculovirus expression system. Recombinant HDAC1 forms a complex with endogenous HSP70 and is co-purified with tubulin. The identity of Hsp70 and tubulin was confirmed by MALDITOF mass spectrometry.
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). 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

Entity	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	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	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	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	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	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	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	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	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	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	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	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	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).

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