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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Histone deacetylases (HDAC) are a superfamily of zinc-dependent enzymes that have varying biological roles; they are subclassified into four groups, i.e. I, Ha, IIb, and IV [102]. HDAC inhibitors have been used successfully in vitro and in vivo in the treatment of a wide variety of malignancies. In fact, Vorinostat was the first HDAC inhibitor to receive FDA approval for the treatment of cutaneous T-cell lymphoma [103]. It has since been shown to improve median overall survival in recurrent glioblastoma multiforme and advanced non-small cell lung cancer [104, 105]. However, this drug is a non-specific HDAC inhibitor of all classes of HDACs. Given the varying important biological functions of HDACs, global inhibition can be associated with important side effects. Thus, an impetus exists for selective targeting of HDACs. Chromatin immunoprecipitation assays have confirmed an MYC binding motif in the HDAC2 promoter region; hence, MYC-amplified tumors would serve as good targets for selective HDAC2 inhibitors [106]. In fact, depletion of HDAC2 in medulloblastoma has been shown to be cytotoxic [106]. The class Ila HDACs, HDAC5 and 9, have been shown to be upregulated in patients with aggressive high-risk medulloblastoma [107]. In turn, silencing HDAC5 and 9 expressions via siRNA led to a reduction in medulloblastoma tumor cell growth in vitro [107].
The Role of Epigenetics in Skeletal Muscle Adaptations to Exercise and Exercise Training
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Emerging evidence suggests that histone modifications could also be an important epigenetic mechanism contributing to exercise-induced transcriptional responses in skeletal muscle. Global histone 3 acetylation at lysine 36 is increased immediately following 60 min of cycling in human skeletal muscle and is associated with the nuclear export of the class IIa histone deacetylases (HDACs) (41). This sub-family of HDACs does not possess activity against acetylated lysine, but acts as scaffolds to recruit transcriptional co-repressors and other HDAC isoforms to specific transcription factors (18), such as MEF2 (45). The phosphorylation-dependent nuclear export of the class IIa HDACs disrupts this transcriptional co-repressor complex, resulting in transcription factor–specific gene expression responses (45). The importance of disrupting this co-repressor complex for the transcriptional response to exercise has been highlighted in a recent study (19). Skeletal muscle expression of HDAC4 and HDAC5 mutants that have impaired recruitment of the co-repressor complex results in an exercise-like transcriptional response and enhanced capacity for lipid oxidation (19). Phosphorylation of the class IIa HDACs appears to be regulated by a number of kinases, including the AMP-activated protein kinase (AMPK) (44), the calcium/calmodulin-dependent protein kinase II (CaMKII), and protein kinase D (PKD) (12), in a redundant fashion (43). These studies delineate important signalling pathways by which exercise can induce specific transcriptional responses through epigenetic mechanisms.
Definition, risk factors, and epidemiology of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Other abundant factors in bone tissue include members of the histone deacetylase (HDAC) family (HDAC1, HDAC3, HDAC5, and HDAC9), whereas HDAC5 inhibits Runx2 activity and HDAC9 inhibits peroxisome proliferator-activated receptor gamma (PPAR-γ) and RANKL-reducing osteoclastogenesis. Other factors modulating Runx2 expression are fibroblast growth factors (FGFR2s) and HOXA10 (59).
Histone deacetylase inhibitors as a potential new treatment for psoriatic disease and other inflammatory conditions
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Jehan Mohammad Nazri, Katerina Oikonomopoulou, Elvin D. de Araujo, Dziyana Kraskouskaya, Patrick T. Gunning, Vinod Chandran
As mentioned previously, HDACs are enzymes that function to remove acetyl groups from lysine residues of proteins in a process called deacetylation. These proteins, also known as substrates, can be classified as either histone or non-histone. Briefly, in humans, there have been four families of histones identified: H1, H2 (H2A and H2B), H3, and H4. Early studies demonstrated that HDAC1, HDAC2, HDAC4, HDAC5, and HDAC6 all lack specificity and were able to deacetylate all four core histone proteins, that is, H2A, H2B, H3, and H4 [116]. However, later experimental results indicate that there may be an issue of substrate specificity and preference by HDACs when it comes to deacetylating histones, although this is yet to be fully established [117,118]. For instance, HDAC6 has now been found to have no in vivo activity against histones by way of nuclear deacetylation [119], while HDACs 4, 5, and 7 all show low activity in their catalytic domains [120]. Similarly, non-histone substrates of HDACs are also the subject of intense study. To date, a comprehensive list of non-histone substrates for each HDAC and their specific functional consequences have not been fully characterized although several studies have identified some non-histone substrates for a few HDACs [115,121–123]. Among these non-histone substrates identified are transcription factors, hormone receptors, signal transducers, chaperone proteins, and proteins of the cytoskeleton network.
Effects of Dietary Phytochemicals on DNA Damage in Cancer Cells
Published in Nutrition and Cancer, 2023
Yang Ye, Ying Ma, Mei Kong, Zhihua Wang, Kang Sun, Fang Li
Sulforaphane (SFN) is a member of the isothiocyanate family and derived primarily from the buds of cruciferous vegetables. SFN is used to treat various diseases such as neurodegenerative, kidney, and liver diseases (109–111). SFN is a promising chemotherapy drug; it induces DNA damage, cell cycle arrest, apoptosis, and autophagy in various cancers. Furthermore, SFN induces intracellular ROS generation by disrupting the dynamic balance between glutathione and oxidized glutathione and DNA damage in a concentration-dependent manner, leading to cell cycle arrest in esophageal squamous cell carcinoma (112). In HepG2 cells, SFN inhibits HDAC5 and HDAC11 expression and induces G2/M cell cycle arrest (30). HDAC5 is downregulated by DNA damage and autophagy (113). SFN plays a similar role in other cancers such as colon cancer (114) and osteosarcoma (115). However, in some types of normal human cells, low concentrations of SFN protect cells from DNA damage by mutagens such as pesticide mixtures (116). Therefore, SFN plays a key role in tumor chemoprevention.
Epigenetic master regulators HDAC1 and HDAC5 control pathobiont Enterobacteria colonization in ileal mucosa of Crohn’s disease patients
Published in Gut Microbes, 2022
Mélissa Chervy, Adeline Sivignon, Flavie Dambrine, Anthony Buisson, Pierre Sauvanet, Catherine Godfraind, Matthieu Allez, Lionel Le Bourhis, Nicolas Barnich, Jérémy Denizot
AIEC bacteria were identified by phenotypical characterization in CD patients’ ileal samples from the REMIND cohort and patients were split into three groups: Enterobact -: patients non-colonized by Enterobacteria (n = 95), MAEC +: patients colonized by mucosa-associated E. coli (MAEC) (n = 51), AIEC +: patients colonized by AIEC (n = 25). HDAC5 expression level was studied by immunostaining. We observed that the intensity of HDAC5 signal was higher in AIEC + patients compared to MAEC + patients and patients non-colonized by Enterobacteria (Enterobact -: 44.4% of samples with signal intensity ≥2, MAEC +: 55.6% of samples with signal intensity ≥2 vs AIEC +: 88.9% of samples with signal intensity ≥2), demonstrating an association between HDAC5 high expression and AIEC colonization (Figure 4e and Figure S7). Interestingly, the HDAC1/HDAC5 ratio expression was significantly lower in AIEC-carrier CD patients compared to MAEC+ CD patients and patients non-colonized by Enterobacteria (figure 4f). These observations suggest that low HDAC1 expression and high HDAC5 expression could favor AIEC selection and colonization in CD patients and that imbalance between HDAC1 and HDAC5 expression could predispose CD patients to be colonized by AIEC bacteria. Also, the HDAC1/HDAC5 ratio expression negatively correlated with Enterobacteria load associated with inflamed ileal mucosa (p = .0315), suggesting that HDAC1/HDAC5 ratio expression could be predictive of the Enterobacteria load and AIEC colonization in CD patients (Figure 4g).