CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle.
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.
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
Dalia
D
Ali
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
Hassan
H
Alshammari
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
Radhakrishnan
R
Vishnubalaji
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
Elna Paul
EP
Chalisserry
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
Rimi
R
Hamam
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
Musaad
M
Alfayez
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .|2 Molecular Endocrinology Unit (KMEB), Department of Endocrinology, University Hospital of Odense and University of Southern Denmark , Odense, Denmark .
Moustapha
M
Kassem
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .|3 Prince Naif Health Research Center, King Saud University , Riyadh, Saudi Arabia .
Abdullah
A
Aldahmash
1 Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
Nehad M
NM
Alajez
D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011743:Pyrimidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
C576940:CUDC-907; D009025:Morpholines; D011743:Pyrimidines; D006655:Histone Deacetylases
CUDC-907; HDAC; MSCs; PI3K; adipogenesis; epigenetic