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      A small molecular compound CC1007 induces cross-lineage differentiation by inhibiting HDAC7 expression and HDAC7/MEF2C interaction in BCR-ABL1 pre-B-ALL

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          Abstract

          Histone deacetylase 7 (HDAC7), a member of class IIa HDACs, has been described to be an important regulator for B cell development and has a potential role in B cell acute lymphoblastic leukemia (B-ALL). CC1007, a BML-210 analog, is designed to indirectly inhibit class IIa HDACs by binding to myocyte enhancer factor-2 (MEF2) and blocking the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of these targets. In this study, we investigated the anticancer effects of CC1007 in breakpoint cluster region-Abelson 1 fusion gene-negative (BCR-ABL1 ) pre-B-ALL cell lines and primary patient-derived BCR-ABL1 pre-B-ALL cells. CC1007 had obvious antileukemic activity toward pre-B-ALL cells in vitro and in vivo; it also significantly prolonged median survival time of pre-B-ALL-bearing mice. Interestingly, low dose of CC1007 could inhibit proliferation of BCR-ABL1 pre-B-ALL cells in a time-dependent manner not accompanied by significant cell apoptosis, but along with cross-lineage differentiation toward monocytic lineage. From a mechanistic angle, we showed that HDAC7 was overexpressed in BCR-ABL1 pre-B-ALL cells compared to normal bone marrow samples, and CC1007 could reduce the binding of HDAC7 at the promoters of monocyte–macrophage-specific genes via inhibition of HDAC7 expression and HDAC7:MEF2C interaction. These data indicated that CC1007 may be a promising agent for the treatment of BCR-ABL1 pre-B-ALL.

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          The cellular thermal shift assay for evaluating drug target interactions in cells.

          Thermal shift assays are used to study thermal stabilization of proteins upon ligand binding. Such assays have been used extensively on purified proteins in the drug discovery industry and in academia to detect interactions. Recently, we published a proof-of-principle study describing the implementation of thermal shift assays in a cellular format, which we call the cellular thermal shift assay (CETSA). The method allows studies of target engagement of drug candidates in a cellular context, herein exemplified with experimental data on the human kinases p38α and ERK1/2. The assay involves treatment of cells with a compound of interest, heating to denature and precipitate proteins, cell lysis, and the separation of cell debris and aggregates from the soluble protein fraction. Whereas unbound proteins denature and precipitate at elevated temperatures, ligand-bound proteins remain in solution. We describe two procedures for detecting the stabilized protein in the soluble fraction of the samples. One approach involves sample workup and detection using quantitative western blotting, whereas the second is performed directly in solution and relies on the induced proximity of two target-directed antibodies upon binding to soluble protein. The latter protocol has been optimized to allow an increased throughput, as potential applications require large numbers of samples. Both approaches can be completed in a day.
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            The role of histone deacetylases (HDACs) in human cancer.

            The balance of histone acetylation and deacetylation is an epigenetic layer with a critical role in the regulation of gene expression. Histone acetylation induced by histone acetyl transferases (HATs) is associated with gene transcription, while histone hypoacetylation induced by histone deacetylase (HDAC) activity is associated with gene silencing. Altered expression and mutations of genes that encode HDACs have been linked to tumor development since they both induce the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell-cycle regulation and apoptosis. Thus, HDACs are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors.
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              HDAC family: What are the cancer relevant targets?

              Histone deacetylases comprise a family of 18 genes, which are grouped into classes I-IV based on their homology to their respective yeast orthologues. Classes I, II, and IV consist of 11 family members, which are referred to as "classical" HDACs, whereas the 7 class III members are called sirtuins. Classical HDACs are a promising novel class of anti-cancer drug targets. First HDAC inhibitors have been evaluated in clinical trials and show activity against several cancer diseases. However, these compounds act unselectively against several or all 11 HDAC family members. As a consequence, clinical phase I trials document a wide range of side effects. Therefore, the current challenge in the field is to define the cancer relevant HDAC family member(s) in a given tumor type and to design selective inhibitors, which target cancer cells but leave out normal cells. Knockout of single HDAC family members in mice produces a variety of phenotypes ranging from early embryonic death to viable animals with only discrete alterations, indicating that potential side effects of HDAC inhibitors depend on the selectivity of the compounds. Recently, several studies have shown that certain HDAC family members are aberrantly expressed in several tumors and have non-redundant function in controlling hallmarks of cancer cells. The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease.
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                Author and article information

                Contributors
                zgsllzy@163.com
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                10 September 2020
                10 September 2020
                September 2020
                : 11
                : 9
                : 738
                Affiliations
                [1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Hematology, The Second Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [2 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Institute of Molecular Hematology, , Central South University, ; Changsha, Hunan China
                [3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Oncology, The Second Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [4 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Geriatrics, The Second Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [5 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital & State Key Laboratory of Medical Genetics, , Central South University, ; Changsha, Hunan China
                [6 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Hematology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, , Central South University, ; Zhuzhou, Hunan China
                [7 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Molecular and Computational Biology Program, Department of Biological Sciences, , University of Southern California, ; Los Angeles, CA 90089 USA
                Article
                2949
                10.1038/s41419-020-02949-1
                7483467
                53ebf379-9fad-4ca1-8d98-25bdca69e973
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 22 March 2020
                : 9 August 2020
                : 27 August 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81470323
                Award ID: 81600183
                Award ID: 81500171
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Cell biology
                acute lymphocytic leukaemia,translational research
                Cell biology
                acute lymphocytic leukaemia, translational research

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