Histone deacetylase inhibitor trichostatin A enhances myogenesis by coordinating muscle regulatory factors and myogenic repressors

Hagiwara, Hiroki; Saito, Fumiaki; Masaki, Toshihiro; Ikeda, Miki; Nakamura-Ohkuma, Ayami; Shimizu, Teruo; Matsumura, Kiichiro

doi:10.1016/j.bbrc.2011.10.036

Cited by 18 publications

(17 citation statements)

References 24 publications

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“…5-aza-dC restored expression of the gene, whereas TSA did not. However, as expected, TSA treatment caused increased expression of ID1 gene that was tested as a positive control for TSA treatment [32][33][34], further confirming a role of DNA methylation rather than histone acetylation in regulating expression of the AURKC gene (Fig. 3e, f).…”

Section: Restoration Of Aurkc Expression Correlated With Demethylatiosupporting

confidence: 57%

Regulation of AURKC expression by CpG island methylation in human cancer cells

Fujii

Srivastava²,

Hegde

et al. 2015

Tumor Biol.

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AURKC, a member of the Aurora kinase gene family, is highly expressed in testis but is either moderately expressed or repressed in most somatic cells. Varying expression of AURKC has been observed in human cancers, but the underlying mechanisms of differential expression have been investigated only to a limited extent. We investigated the role of promoter CpG methylation in the regulation of AURKC gene expression in human cancer cells, in relation to a recently reported AURKC transcription repressor PLZF/ZBTB16, implicated in transformation and tumorigenesis. AURKC and PLZF/ZBTB16 expression profiles were investigated in reference to CpG methylation status on the AURKC promoter experimentally, and also in The Cancer Genome Atlas (TCGA) dataset involving multiple cancer types. AURKC promoter showed dense to moderate hypermethylation correlating with low to moderate expression of the gene in normal somatic cells and cancer cell lines, while testis with high expression revealed marked hypo-methylation. Treatment with the demethylating agent, 5-aza-dC, but not the histone deacetylase (HDAC) inhibitor, TSA, led to elevated expression in cancer cell lines, indicating that promoter DNA methylation negatively regulates AURKC expression. High expression of PLZF in PLZF-transfected cells treated with 5-aza-dC only partially repressed expression of AURKC despite 5-aza-dC also inducing elevated PLZF expression. Analyses of the TCGA data showed differential expression of AURKC in multiple cancer types and stronger correlation of AURKC expression with CpG methylation compared to PLZF levels. These findings demonstrate that differential promoter CpG methylation is an important mechanism regulating AURKC expression in cancer cells.

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Section: Restoration Of Aurkc Expression Correlated With Demethylatiosupporting

confidence: 57%

Regulation of AURKC expression by CpG island methylation in human cancer cells

Fujii

Srivastava²,

Hegde

et al. 2015

Tumor Biol.

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“…Interestingly, TSA treatment is also beneficial in the Smn 2B/− mouse model that does not harbor the SMN2 transgene; however in this case there was no detectable increase in Smn. Furthermore, other studies have demonstrated that TSA treatment of C2C12 cells increased myoblast fusion, and that TSA can increase the expression of early myogenic regulatory factors (18,19). We therefore investigated whether TSA could increase myofiber size and ameliorate muscle maturity in Smn 2B/− mice.…”

Section: Resultsmentioning

confidence: 93%

“…Primary myoblasts seeded at equal density were induced to differentiate with Dulbecco’'s Modified Eagle Medium (Wisent) supplemented with 5% horse serum (Gibco) and 1% penicillin/streptomycin. To assess the impact of TSA on fusion, Smn 2B/− myoblasts were treated with 100 n m of TSA for 24 h and then induced to differentiate for 72 h as previously described (19). In all experiments, cells were maintained at 37°C with 5% CO 2 and were provided fresh media every other day.…”

Section: Methodsmentioning

confidence: 99%

Myogenic program dysregulation is contributory to disease pathogenesis in spinal muscular atrophy

Boyer

Deguise

Murray

et al. 2014

Human Molecular Genetics

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Mutations in the survival motor neuron (SMN1) gene lead to the neuromuscular disease spinal muscular atrophy (SMA). Although SMA is primarily considered as a motor neuron disease, the importance of muscle defects in its pathogenesis has not been fully examined. We use both primary cell culture and two different SMA model mice to demonstrate that reduced levels of Smn lead to a profound disruption in the expression of myogenic genes. This disruption was associated with a decrease in myofiber size and an increase in immature myofibers, suggesting that Smn is crucial for myogenic gene regulation and early muscle development. Histone deacetylase inhibitor trichostatin A treatment of SMA model mice increased myofiber size, myofiber maturity and attenuated the disruption of the myogenic program in these mice. Taken together, our work highlights the important contribution of myogenic program dysregulation to the muscle weakness observed in SMA.

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“…To elucidate the mechanism of enhanced contractile force generation in TSA-treated tissue constructs, we examined follistatin expression after TSA treatment. TSA is one of the most potent HDAC inhibitors in myoblasts, and several groups have reported the effects of TSA on myogenic differentiation2328. Using microarray analysis, Iezzi et al .…”

Section: Discussionmentioning

confidence: 99%

In vitro drug testing based on contractile activity of C2C12 cells in an epigenetic drug model

Ikeda

Ito

Imada

et al. 2017

Sci Rep

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Skeletal muscle tissue engineering holds great promise for pharmacological studies. Herein, we demonstrated an in vitro drug testing system using tissue-engineered skeletal muscle constructs. In response to epigenetic drugs, myotube differentiation of C2C12 myoblast cells was promoted in two-dimensional cell cultures, but the levels of contractile force generation of tissue-engineered skeletal muscle constructs prepared by three-dimensional cell cultures were not correlated with the levels of myotube differentiation in two-dimensional cell cultures. In contrast, sarcomere formation and contractile activity in two-dimensional cell cultures were highly correlated with contractile force generation of tissue-engineered skeletal muscle constructs. Among the epigenetic drugs tested, trichostatin A significantly improved contractile force generation of tissue-engineered skeletal muscle constructs. Follistatin expression was also enhanced by trichostatin A treatment, suggesting the importance of follistatin in sarcomere formation of muscular tissues. These observations indicate that contractility data are indispensable for in vitro drug screening.

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Histone deacetylase inhibitor trichostatin A enhances myogenesis by coordinating muscle regulatory factors and myogenic repressors

Cited by 18 publications

References 24 publications

Regulation of AURKC expression by CpG island methylation in human cancer cells

Regulation of AURKC expression by CpG island methylation in human cancer cells

Myogenic program dysregulation is contributory to disease pathogenesis in spinal muscular atrophy

In vitro drug testing based on contractile activity of C2C12 cells in an epigenetic drug model

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