Recent Progress in Histone Deacetylase (HDAC) 1 Inhibitors as Anticancer Agent.

Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC1 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC1 displays a unique structure primarily found in the nucleus and involved in epigenetic and transcriptional regulation. HDAC1 is ubiquitously expressed and associated with Sin3, NuRD, and CoRest transcription repressive complexes responsible for distinct cellular processes like cell proliferation and survival. HDAC1 inhibitors have been effectively used to treat various cancers such as gastric, breast, colorectal, prostate, colon, lung, ovarian, pancreatic, and inflammation without exerting significant toxic effects. In this review, we summarize four major structural classes of HDAC1 inhibitors (i.e., hydroxamic acid derivatives, benzamides, hydrazides, and thiols) with their structural activity relationship. This review is a comprehensive work on HDAC1 inhibitors to achieve deep insight of knowledge about the structural information of HDAC1 inhibitors. It may provide up-to-date direction for developing new selective HDAC1 inhibitors as anticancer agents.

Clinical significance of enhancer of zeste homolog 2 and histone deacetylases 1 and 2 expression in peripheral T-cell lymphoma.

Epigenetics serve a key role in peripheral T cell lymphoma (PTCL). The purpose of the present study was to investigate the clinical significance of enhancer of zeste homolog 2 (EZH2) and histone deacetylase 1 and 2 (HDAC1/2) expression in PTCL. A total of 82 patients were enrolled in the present study, including 43 with PTCL not otherwise specified (PTCL-NOS), 10 with angioimmunoblastic T-cell lymphoma (AITL), 14 with natural killer/T-cell lymphoma (NK/TCL) and 15 with anaplastic large cell lymphoma (ALCL). EZH2 and HDAC1/2 expression was detected by immunohistochemistry and any correlations between them were evaluated. Additionally, any correlations between EZH2 or HDAC1/2 expression and a number of clinicopathological characteristics were analyzed, and survival curves were created. Results revealed that 55.8% of patients with PTCL-NOS, 57.1% of patients with NK/TCL, 86.7% of patients ALCL and 50% of patients with AITL highly expressed HDAC1. Furthermore, 58.1% of patients with PTCL-NOS, 57.1% of patients with NK/TCL, 53.3% of patients with ALCL and 60% of patients with AITL highly expressed HDAC2. Additionally, 67.5% of patients with PTCL-NOS, 50% of patients with NK/TCL, 73.3% of patients with ALCL and 60% of patients with AITL highly expressed EZH2. EZH2 expression was significantly correlated with the presence of B symptoms, elevated LDH and elevated ß2 microglobulin (B2M; P<0.05), and HDAC2 expression was significantly correlated with sex, advanced clinical stages, high international prognostic index scores and elevated B2M levels (P<0.05) in all the patients with PTCL. However, different subtypes of PTCL are correlated with different clinical characteristics. Patients with PTCL highly expressing EZH2 or HDAC2 exhibit a poorer overall survival rate. In conclusion, EZH2 and HDAC1/2 were frequently upregulated in patients with PTCL, and the patients with a higher EZH2 and HDAC2 expression usually exhibited a poorer survival rate. Therefore, EZH2 and HDAC2 may be prognostic markers in patients with PTCL, particularly in those with PTCL-NOS.

Ubiquitin-specific protease 4 (USP4) suppresses myoblast differentiation by down regulating MyoD activity in a catalytic-independent manner.

For myotube formation, proliferation and differentiation of myoblasts must be tightly regulated by various myogenic regulatory factors (MRFs) such as MyoD, myogenic factor 5 (Myf5), myogenin, and muscle-specific regulatory factor 4 (MRF4). However, it is not clear how the expression or activity of these MRFs is controlled during myogenesis. In this study, we identified ubiquitin-specific protease 4 (USP4), one of deubiquitinating enzymes, as a suppressor of MRFs by demonstrating that a knockdown of USP4 enhances myogenesis by controlling MyoD and the level of myogenesis marker proteins in C2C12 cells. However, it was revealed that the effect of USP4 on myogenesis is independent of its deubiquitinase activity because the catalytic-site mutant has the same inhibitory effects as the wild-type USP4 on myogenesis. We observed that the activity and protein levels of both HDAC1 and HDAC4 are decreased when myoblast differentiation is promoted by the USP4 knockdown. We also found that the role of USP4 in muscle differentiation is correlated with two major signaling pathways in myogenesis, AKT and the p38 mitogen-activated protein kinase pathways. According to these results, we propose that USP4 is a key player in myogenic differentiation; it controls myogenic regulatory factors in a catalytic-independent manner.

Neonatal Maternal Separation Impairs Prefrontal Cortical Myelination and Cognitive Functions in Rats Through Activation of Wnt Signaling.

Adverse early-life experience such as depriving the relationship between parents and children induces permanent phenotypic changes, and impairs the cognitive functions associated with the prefrontal cortex (PFC). However, the underlying mechanism remains unclear. In this work, we used rat neonatal maternal separation (NMS) model to illuminate whether and how NMS in early life affects cognitive functions, and what the underlying cellular and molecular mechanism is. We showed that rat pups separated from their dam 3 h daily during the first 3 postnatal weeks alters medial prefrontal cortex (mPFC) myelination and impairs mPFC-dependent behaviors. Myelination appears necessary for mPFC-dependent behaviors, as blockade of oligodendrocytes (OLs) differentiation or lysolecithin-induced demyelination, impairs mPFC functions. We further demonstrate that histone deacetylases 1/2 (HDAC1/2) are drastically reduced in NMS rats. Inhibition of HDAC1/2 promotes Wnt activation, which negatively regulates OLs development. Conversely, selective inhibition of Wnt signaling by XAV939 partly rescue myelination arrestment and behavior deficiency caused by NMS. These findings indicate that NMS impairs mPFC cognitive functions, at least in part, through modulation of oligodendrogenesis and myelination. Understanding the mechanism of NMS on mPFC-dependent behaviors is critical for developing pharmacological and psychological interventions for child neglect and abuse.

The Effect of Histone Deacetylases-1 siRNA on the Growth and Apoptosis of HeLa Cells / 华中科技大学学报(医学版)

Objective To investigate the effect of histone deacetylases-1(HDAC-1)siRNA on the HDAC-1 protein expression,cell growth and apoptosis in HeLa cells.Methods The HDAC-1 protein was knocked down by HDAC-1 siRNA.HDAC-1 protein was detected by Western blot.The cell growth inhibition was assesses by MTT and clone forming assay.Apoptosis was measured by flow cytometry.Results Forty-eight h after transfection of HDAC-1 siRNA,HDAC-1 protein expression in HeLa cells was down-regulated obviously.The down-regulation of HDAC-1 significantly reduced the colony formation rate,inhibited cell proliferation and induced apoptosis in HeLa cells.Conclusion HDAC-1 siRNA may play an anti-proliferation role in HeLa cells by inducing apoptosis.