Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

Wu, Donglu; Qiu, Ye; Jiao, Yunshuang; Qiu, Zhidong; Li, Da

doi:10.3389/fonc.2020.560487

Cited by 49 publications

(27 citation statements)

References 201 publications

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“…Histone acetylation is one of the most extensively studied epigenetic modifications, and it plays key roles in chromatin remodeling and gene regulation and is mainly regulated by HAT and HDAC [ 27 ]. In this study, we found that HDAC3 expression was increased in calcified ACP tissue, and inhibition of HDAC3 enhanced ACP cell calcification.…”

Section: Discussionmentioning

confidence: 99%

CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma

et al. 2022

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Background Calcification of adamantinomatous craniopharyngioma (ACP) often causes problems with tumor resection, leading to a high incidence of deadly complications and tumor recurrence. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are 2 key enzymes that regulate histone acetylation and play important roles in tumor development. However, the roles of HAT and HDAC in the calcification and osteoblastic differentiation of ACP are not known. Methods In this study, primary cells were isolated from ACP tissues, and calcification was induced with bone morphogenetic protein 2 (Bmp2). HDAC3 expression was assessed in 12 tissue samples by Western blotting and immunohistochemistry. ACP calcification was assessed by Alizarin red staining. A luciferase reporter assay was performed to examine the interaction between miR-181b and the 3’-untranslated region of the polycomb chromobox 4 (CBX4) gene. Results Our results showed that the expression of HDAC3 was increased in the calcified ACP samples, but inhibition of HDAC3 promoted ACP cell calcification and osteoblastic differentiation. Mechanistically, HDAC3 nuclear translocation was suppressed by Bmp2, leading to Runx2 protein expression and Osterix, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP) mRNA expression. In addition, this process was suppressed by CBX4, which stabilized the nuclear localization of HDAC3. miR-181b, the expression of which was increased in Bmp2-induced ACP cells, directly targeted and decreased CBX4 expression and inhibited the nuclear localization of HDAC3. Conclusions Our results demonstrate that Bmp2 increases miR-181b levels to directly target and inhibit CBX4 expression, leading to a reduction in the CBX4-dependent regulation of HDAC3 nuclear translocation, which results in Runx2 activation/osteoblastic differentiation and calcium deposition in ACP. Further studies targeting these cascades may contribute to therapeutic interventions used for recurrent ACP.

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Section: Discussionmentioning

confidence: 99%

CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma

et al. 2022

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“…Gene transcription is finely tuned by the interaction of DNA with histone proteins that are organized in chromatin fibers. In the last few years, a number of drugs has been developed to regulate these interactions [ 141 , 142 , 143 ], including the inhibiting histone deacetylases (HDACs) that remove acetyl groups from the N-terminal lysine of nucleosome histones [ 144 ]. In principle, since histone deacetylation leads to gene silencing, it is reasonable to predict that HDAC inhibitors can upregulate TAA expression.…”

Section: Drug-induced Upregulation Of Tumor Immunogenicitymentioning

confidence: 99%

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

Franzese

Torino

Giannetti

et al. 2021

IJMS

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The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients’ quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in the near future. In view of the crucial role that is played by tumor immunity, the present review provides essential information on the immune-mediated effects potentially generated by the interplay between ionizing radiation and cytotoxic antitumor agents when interacting with target malignant cells. Therefore, the radiation-dependent abscopal effect (i.e., a biological effect of ionizing radiation that occurs outside the irradiated field), the influence of cancer chemotherapy on the antigenic pattern of target neoplastic cells, and the immunogenic cell death (ICD) caused by anticancer agents are the main topics of this presentation. It is widely accepted that tumor immunity plays a fundamental role in generating an abscopal effect and that anticancer drugs can profoundly influence not only the host immune responses, but also the immunogenic pattern of malignant cells. Remarkably, several anticancer drugs impact both the abscopal effect and ICD. In addition, certain classes of anticancer agents are able to amplify already expressed tumor-associated antigens (TAA). More importantly, other drugs, especially triazenes, induce the appearance of new tumor neoantigens (TNA), a phenomenon that we termed drug-induced xenogenization (DIX). The adoption of the abscopal effect is proposed as a potential therapeutic modality when properly applied concomitantly with drug-induced increase in tumor cell immunogenicity and ICD. Although little to no preclinical or clinical studies are presently available on this subject, we discuss this issue in terms of potential mechanisms and therapeutic benefits. Upcoming investigations are aimed at evaluating how chemical anticancer drugs, radiation, and immunotherapies are interacting and cooperate in evoking the abscopal effect, tumor xenogenization and ICD, paving the way for new and possibly successful approaches in cancer therapy.

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“…Protein acetylation is a dynamic process that is controlled by histone acetyltransferases and histone deacetylases. Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from a donor molecule to a target lysine residue, leading to protein acetylation, while histone deacetylases (HDACs) catalyze removal of acetyl groups from lysine residues, causing protein deacetylation ( Verdin and Ott, 2015 ; Wu et al, 2020 ). Moreover, acetylation is regulated by a family of the bromodomain and extra-terminal (BET) proteins, which can recognize the acetylated lysine in histones and other proteins ( Cochran et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Histone Acetylation and Modifiers in Renal Fibrosis

Shen

Zhuang

2022

Front. Pharmacol.

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Histones are the most abundant proteins bound to DNA in eukaryotic cells and frequently subjected to post-modifications such as acetylation, methylation, phosphorylation and ubiquitination. Many studies have shown that histone modifications, especially histone acetylation, play an important role in the development and progression of renal fibrosis. Histone acetylation is regulated by three families of proteins, including histone acetyltransferases (HATs), histone deacetylases (HDACs) and bromodomain and extraterminal (BET) proteins. These acetylation modifiers are involved in a variety of pathophysiological processes leading to the development of renal fibrosis, including partial epithelial-mesenchymal transition, renal fibroblast activation, inflammatory response, and the expression of pro-fibrosis factors. In this review, we summarize the role and regulatory mechanisms of HATs, HDACs and BET proteins in renal fibrosis and provide evidence for targeting these modifiers to treat various chronic fibrotic kidney diseases in animal models.

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Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

Cited by 49 publications

References 201 publications

CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma

CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

Histone Acetylation and Modifiers in Renal Fibrosis

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