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Epigenetic Library Screen Identifies Abexinostat As Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells

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Epigenetic Library Screen Identifies Abexinostat As Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells University of Southern Denmark Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells Ali, D.; Hamam, R.; Alfayez, M.; Kassem, Moustapha; Aldahmash, Abdullah; Alajez, Nehad M Published in: Stem Cells Translational Medicine DOI: 10.5966/sctm.2015-0331 Publication date: 2016 Document version: Final published version Citation for pulished version (APA): Ali, D., Hamam, R., Alfayez, M., Kassem, M., Aldahmash, A., & Alajez, N. M. (2016). Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells Translational Medicine, 5(8), 1036-1047. https://doi.org/10.5966/sctm.2015-0331 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 06. Oct. 2021 Cell-Based Drug Development, Screening, and Toxicology CELL-BASED DRUG DEVELOPMENT,SCREENING, AND TOXICOLOGY Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells DALIA ALI,a RIMI HAMAM,a MUSAED ALFAYEZ,a MOUSTAPHA KASSEM,a,b ABDULLAH ALDAHMASH,a,c NEHAD M. ALAJEZa Key Words. Epigenetic x Adipocyte x Osteoblast x Mesenchymal stem cells x Histone deacetylase inhibitors aStem Cell Unit, Department ABSTRACT of Anatomy, College of The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchy- Medicine, and cPrince Naif mal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, Health Research Center, King we performed an epigenetic library functional screen and identified several novel compounds, in- Saud University, Riyadh, cluding abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using Kingdom of Saudi Arabia; gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high- bMolecular Endocrinology throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell proliferation and differentiation that were targeted by abexinostat. Concor- and Stem Cell Research Unit, dantly, ChIP-quantitative polymerase chain reaction revealed marked increase in H3K9Ac epigenetic Department of mark on the promoter region of AdipoQ, FABP4, PPARg, KLF15, CEBPA, SP7, and ALPL in abexinostat- Endocrinology, University of treated hMSCs. Pharmacological inhibition of focal adhesion kinase (PF-573228) or insulin-like growth Southern Denmark, Odense, factor-1R/insulin receptor (NVP-AEW51) signaling exhibited significant inhibition of abexinostat- Denmark mediated adipocytic differentiation, whereas inhibition of WNT (XAV939) or transforming growth factor-b (SB505124) signaling abrogated abexinostat-mediated osteogenic differentiation of hMSCs. Correspondence: Nehad M. Our findings provide insight into the understanding of the relationship between the epigenetic effect Alajez, Ph.D., Stem Cell Unit, Department of Anatomy, College of histone deacetylase inhibitors, transcription factors, and differentiation pathways governing adi- of Medicine, King Saud pocyte and osteoblast differentiation. Manipulating such pathways allows a novel use for epigenetic University, P.O. Box 305713, compounds in hMSC-based therapies and tissue engineering. STEM CELLS TRANSLATIONAL MEDICINE Riyadh 11461, Kingdom of Saudi 2016;5:1036–1047 Arabia. Telephone: 966 114679216; E-Mail: nalajez@ksu. edu.sa SIGNIFICANCE Received November 5, 2015; This unbiased epigenetic library functional screen identified several novel compounds, including accepted for publication March abexinostat, that promoted adipocytic and osteoblastic differentiation of human skeletal (mesenchy- 10, 2016; published Online First on May 18, 2016. mal or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, ©AlphaMed Press and differentiation pathways controlling adipocyte and osteoblast differentiation of hMSCs. Manip- 1066-5099/2016/$20.00/0 ulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies for tis- http://dx.doi.org/ sue engineering, bone disease, obesity, and metabolic-disorders. 10.5966/sctm.2015-0331 INTRODUCTION remodeling [2]. Nevertheless, it has been report- ed in several studies that epigenetic modulations Human skeletal stem cells (also known as stromal could affect key transcriptional factors shaping or mesenchymal stem cells) (hMSCs) are adult gene expression and differentiation potentials multipotent stem cells that have the potential of embryonic stem cells [3]. The modulation of to differentiate into distinct mesodermal lineage chromatin structure through histone modifica- cells, such as adipocytes, osteoblasts, chondro- tions includes acetylation, methylation and phos- cytes, and myocytes [1]. phorylation, and this modulation is referred to Lineage-specific differentiation of MSCs is collectively as epigenetic regulation [4]. determined by integrating microenvironmental Epigenetic modulation refers to modulation cues with intracellular signaling pathways, tran- of heritable changes in gene expression via scriptional regulatory networks, and chromatin mechanisms other than alteration of the DNA STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1036–1047 www.StemCellsTM.com ©AlphaMed Press 2016 Ali, Hamam, Alfayez et al. 1037 sequence [5]. Histone acetylation is regulated by a balance of Table 1. Characteristics of the 24 compounds used in the epigenetic the enzymatic activity of histone acetyltransferase and histone library screen deacetylase (HDAC) [6]. The two opposing enzymatic activities No. Name of compound Target of histone acetylation and deacetylation are important for the 1 Quisinostat HDAC1, HDAC2, HDAC4, activation of transcription [7] and regulation of gene expression HDAC10, HDAC11 in eukaryotes [8]. HDACs regulate cell differentiation and mod- 2 Givinostat HD2, HD1B and HD1A ulate tissue-specific gene expressions, as has been demon- 3 Panobinostat HDAC, HDAC strated in the development of neuron precursors in animal studies [9] and in clinical trials as antiproliferative and proapop- 4 Trichostatin A HDAC totic therapy against cancer [10, 11]. 5 Vorinostat HDAC Several studies investigated the importance of chemical com- 6 Obatoclax mesylate Bcl-2 pound inhibitors of HDACs for their possible therapeutic effects. 7 Belinostat HDAC Inhibitors of HDACs (HDACi) induce hyperacetylation of histones, 8 Abexinostat HDAC1, HDAC2, HDAC3, followed by the activation of specific genes through relaxation of HDAC6, HDAC8, DAC10 the DNA conformation. Some HDACi have been tested for their 9 Dacinostat HDAC anticancer effects in different human malignancies [12, 13]. In ad- 10 Mocetinostat HDAC1, HDAC2, HDAC3 dition, several studies investigated the effect of HDACi on stem cell differentiation. HDACi enhanced osteoblast differentiation 11 CUDC-907 PI3Ka, HDAC1, HDAC2, HDAC3, HDAC10 of human dental pulp stem cells [14] and bone marrow MSCs [10]. Dudakovic et al. [15] reported that HDACi promoted late 12 M344 HDAC stages of osteoblast differentiation via increasing histone H4 acet- 13 Tacedinaline HDAC1 ylation and regulating insulin signaling pathway inmurine MC3T3. 14 SRT1720 SIRT1 Moreover, the observed promoting effects of HDACi on osteo- 15 CUDC-101 HDAC, EGFR, HER2 blast differentiation have been attributed to their regulatory ef- 16 Droxinostat HDAC3, HDAC6, HDAC8 fects on runt-related-transcription factor 2, a key transcription factor in osteoblast commitment [16–18]. Few studies examined 17 MC1568 HDAC1A, HDAC1B the changes in HDAC during adipocyte differentiation of extrame- 18 Pracinostat HDAC1, HDAC3, HDAC4, dullary fat [19–21]. Little is known about the effects of HDAC and HDAC5, HDAC9, DAC10 HDACi on bone marrow adipocyte differentiation and functions. 19 Selisistat SIRT1 Herein we tested the effects of several chemical compounds 20 AR-42 HDAC with effects on epigenetic state regulators and identified novel 21 Sodium valproate HDAC, Autophagy & GABA compounds with significant effects on adipocyte and osteoblast receptor differentiation of hMSCs. One of these, abexinostat, was chosen 22 PCI-34051 HDAC1, HDAC2, HDAC3, for follow-up studies. Using chromatin immunoprecipitation HDAC6, HDAC8, HDAC10 combined with high-throughput DNA sequencing (ChIP-seq) 23 Romidepsin HDAC1, HDAC2 technology and ChIP quantitative polymerase chain reaction 24 Sirtinol SIRT1, SIRT2 (qPCR), we identified several key genes involved in regulating MSC proliferation and differentiation as putative targets for abexinostat. 110 mg/l 10% sodium pyruvate, 10% fetal bovine serum [FBS], 1% penicillin-streptomycin, and 1% nonessential amino acids). All reagents were
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