CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle

Dalia Ali, Hassan Alshammari, Radhakrishnan Vishnubalaji, Elna Paul Chalisserry, Rimi Hamam, Musaad Alfayez, Moustapha Kassem, Abdullah Aldahmash, Nehad M Alajez

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The role of bone marrow adipocytes (BMAs) in overall energy metabolism and their effects on bone mass are currently areas of intensive investigation. BMAs differentiate from bone marrow stromal cells (BMSCs); however, the molecular mechanisms regulating BMA differentiation are not fully understood. In this study, we investigated the effect of CUDC-907, identified by screening an epigenetic small-molecule library, on adipocytic differentiation of human BMSCs (hBMSCs) and determined its molecular mechanism of action. Human bone marrow stromal cells exposed to CUDC-907 (500 nM) exhibited enhanced adipocytic differentiation (∼2.9-fold increase, P < 0.005) compared with that of control cells. Global gene expression and signaling pathway analyses of differentially expressed genes revealed a strong enrichment of genes involved in adipogenesis, cell cycle, and DNA replication. Chromatin immune precipitation combined with quantitative polymerase chain reaction showed significant increase in H3K9ac epigenetic marker in the promoter regions of AdipoQ, FABP4, PPARγ, KLF15, and CEBPA in CUDC-907-treated hBMSCs. Follow-up experiments corroborated that the inhibition of histone deacetylase (HDAC) activity enhanced adipocytic differentiation, while the inhibition of PI3K decreased adipocytic differentiation. In addition, CUDC-907 arrested hBMSCs in the G0-G1 phase of the cell cycle and reduced the number of S-phase cells. Our data reveal that HDAC, PI3K, and cell cycle genes are important regulators of BMA formation and demonstrate that adipocyte differentiation of hBMSCs is associated with complex changes in a number of epigenetic and genetic pathways, which can be targeted to regulate BMA formation.

OriginalsprogEngelsk
TidsskriftStem Cells and Development
Vol/bind26
Udgave nummer5
Sider (fra-til)353-362
ISSN1547-3287
DOI
StatusUdgivet - 2017

Fingeraftryk

Histone Deacetylases
Adipocytes
Cell Cycle
Mesenchymal Stromal Cells
Epigenomics
cdc Genes
Adipogenesis
Cell Cycle Resting Phase
G1 Phase
Energy Metabolism
CUDC-907
Polymerase Chain Reaction

Citer dette

Ali, D., Alshammari, H., Vishnubalaji, R., Chalisserry, E. P., Hamam, R., Alfayez, M., ... Alajez, N. M. (2017). CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle. Stem Cells and Development, 26(5), 353-362. https://doi.org/10.1089/scd.2016.0183
Ali, Dalia ; Alshammari, Hassan ; Vishnubalaji, Radhakrishnan ; Chalisserry, Elna Paul ; Hamam, Rimi ; Alfayez, Musaad ; Kassem, Moustapha ; Aldahmash, Abdullah ; Alajez, Nehad M. / CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle. I: Stem Cells and Development. 2017 ; Bind 26, Nr. 5. s. 353-362.
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title = "CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle",
abstract = "The role of bone marrow adipocytes (BMAs) in overall energy metabolism and their effects on bone mass are currently areas of intensive investigation. BMAs differentiate from bone marrow stromal cells (BMSCs); however, the molecular mechanisms regulating BMA differentiation are not fully understood. In this study, we investigated the effect of CUDC-907, identified by screening an epigenetic small-molecule library, on adipocytic differentiation of human BMSCs (hBMSCs) and determined its molecular mechanism of action. Human bone marrow stromal cells exposed to CUDC-907 (500 nM) exhibited enhanced adipocytic differentiation (∼2.9-fold increase, P < 0.005) compared with that of control cells. Global gene expression and signaling pathway analyses of differentially expressed genes revealed a strong enrichment of genes involved in adipogenesis, cell cycle, and DNA replication. Chromatin immune precipitation combined with quantitative polymerase chain reaction showed significant increase in H3K9ac epigenetic marker in the promoter regions of AdipoQ, FABP4, PPARγ, KLF15, and CEBPA in CUDC-907-treated hBMSCs. Follow-up experiments corroborated that the inhibition of histone deacetylase (HDAC) activity enhanced adipocytic differentiation, while the inhibition of PI3K decreased adipocytic differentiation. In addition, CUDC-907 arrested hBMSCs in the G0-G1 phase of the cell cycle and reduced the number of S-phase cells. Our data reveal that HDAC, PI3K, and cell cycle genes are important regulators of BMA formation and demonstrate that adipocyte differentiation of hBMSCs is associated with complex changes in a number of epigenetic and genetic pathways, which can be targeted to regulate BMA formation.",
keywords = "Adipogenesis, CUDC-907, Epigenetic, HDAC, MSCs, PI3K",
author = "Dalia Ali and Hassan Alshammari and Radhakrishnan Vishnubalaji and Chalisserry, {Elna Paul} and Rimi Hamam and Musaad Alfayez and Moustapha Kassem and Abdullah Aldahmash and Alajez, {Nehad M}",
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Ali, D, Alshammari, H, Vishnubalaji, R, Chalisserry, EP, Hamam, R, Alfayez, M, Kassem, M, Aldahmash, A & Alajez, NM 2017, 'CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle', Stem Cells and Development, bind 26, nr. 5, s. 353-362. https://doi.org/10.1089/scd.2016.0183

CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle. / Ali, Dalia; Alshammari, Hassan; Vishnubalaji, Radhakrishnan; Chalisserry, Elna Paul; Hamam, Rimi; Alfayez, Musaad ; Kassem, Moustapha; Aldahmash, Abdullah; Alajez, Nehad M.

I: Stem Cells and Development, Bind 26, Nr. 5, 2017, s. 353-362.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle

AU - Ali, Dalia

AU - Alshammari, Hassan

AU - Vishnubalaji, Radhakrishnan

AU - Chalisserry, Elna Paul

AU - Hamam, Rimi

AU - Alfayez, Musaad

AU - Kassem, Moustapha

AU - Aldahmash, Abdullah

AU - Alajez, Nehad M

PY - 2017

Y1 - 2017

N2 - The role of bone marrow adipocytes (BMAs) in overall energy metabolism and their effects on bone mass are currently areas of intensive investigation. BMAs differentiate from bone marrow stromal cells (BMSCs); however, the molecular mechanisms regulating BMA differentiation are not fully understood. In this study, we investigated the effect of CUDC-907, identified by screening an epigenetic small-molecule library, on adipocytic differentiation of human BMSCs (hBMSCs) and determined its molecular mechanism of action. Human bone marrow stromal cells exposed to CUDC-907 (500 nM) exhibited enhanced adipocytic differentiation (∼2.9-fold increase, P < 0.005) compared with that of control cells. Global gene expression and signaling pathway analyses of differentially expressed genes revealed a strong enrichment of genes involved in adipogenesis, cell cycle, and DNA replication. Chromatin immune precipitation combined with quantitative polymerase chain reaction showed significant increase in H3K9ac epigenetic marker in the promoter regions of AdipoQ, FABP4, PPARγ, KLF15, and CEBPA in CUDC-907-treated hBMSCs. Follow-up experiments corroborated that the inhibition of histone deacetylase (HDAC) activity enhanced adipocytic differentiation, while the inhibition of PI3K decreased adipocytic differentiation. In addition, CUDC-907 arrested hBMSCs in the G0-G1 phase of the cell cycle and reduced the number of S-phase cells. Our data reveal that HDAC, PI3K, and cell cycle genes are important regulators of BMA formation and demonstrate that adipocyte differentiation of hBMSCs is associated with complex changes in a number of epigenetic and genetic pathways, which can be targeted to regulate BMA formation.

AB - The role of bone marrow adipocytes (BMAs) in overall energy metabolism and their effects on bone mass are currently areas of intensive investigation. BMAs differentiate from bone marrow stromal cells (BMSCs); however, the molecular mechanisms regulating BMA differentiation are not fully understood. In this study, we investigated the effect of CUDC-907, identified by screening an epigenetic small-molecule library, on adipocytic differentiation of human BMSCs (hBMSCs) and determined its molecular mechanism of action. Human bone marrow stromal cells exposed to CUDC-907 (500 nM) exhibited enhanced adipocytic differentiation (∼2.9-fold increase, P < 0.005) compared with that of control cells. Global gene expression and signaling pathway analyses of differentially expressed genes revealed a strong enrichment of genes involved in adipogenesis, cell cycle, and DNA replication. Chromatin immune precipitation combined with quantitative polymerase chain reaction showed significant increase in H3K9ac epigenetic marker in the promoter regions of AdipoQ, FABP4, PPARγ, KLF15, and CEBPA in CUDC-907-treated hBMSCs. Follow-up experiments corroborated that the inhibition of histone deacetylase (HDAC) activity enhanced adipocytic differentiation, while the inhibition of PI3K decreased adipocytic differentiation. In addition, CUDC-907 arrested hBMSCs in the G0-G1 phase of the cell cycle and reduced the number of S-phase cells. Our data reveal that HDAC, PI3K, and cell cycle genes are important regulators of BMA formation and demonstrate that adipocyte differentiation of hBMSCs is associated with complex changes in a number of epigenetic and genetic pathways, which can be targeted to regulate BMA formation.

KW - Adipogenesis

KW - CUDC-907

KW - Epigenetic

KW - HDAC

KW - MSCs

KW - PI3K

U2 - 10.1089/scd.2016.0183

DO - 10.1089/scd.2016.0183

M3 - Journal article

C2 - 27829312

AN - SCOPUS:85013877976

VL - 26

SP - 353

EP - 362

JO - Stem Cells and Development

JF - Stem Cells and Development

SN - 1547-3287

IS - 5

ER -