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Histone deacetylase (HDAC)

Histone deacetylases (HDACs) can regulate the progression of various cancers, while their roles in glioblastoma multiforme (GBM) are not well known.

HDAC inhibitors that induce acetylation of nuclear histones play a crucial role in gene expression 1).

HDAC inhibitors have radiosensitizing effects in established cancer cell lines, and antiproliferative agents that could be developed into drugs to treat cancer.

The deacetylase inhibitor sodium butyrate (NaBT) has been shown to induce cell cycle arrest or differentiation in various tumor cells 2).

Histone deacetylases (HDACs) play a role in the tumorigenesis of glioblastoma multiforme (GBM), whereas the underlying mechanism has not been elucidated.

see Histone deacetylase 1

see Histone deacetylase 2

see Histone deacetylase 3

see Histone deacetylase 9

see Histone deacetylase 11

GBM cell growth was significantly inhibited by ACY-1215, a specific HDAC6 inhibitor. Further analyses show that HDAC6 may promote growth of GBM cells through inhibition of SMAD2 phosphorylation to downregulate p21. Thus, the data demonstrate a previously unrecognized regulation pathway in that HDAC6 increases GBM growth through attenuating transforming growth factor β (TGFβ) receptor signaling 3).

Pont et al. conducted a study to compare the efficacy of SAHA, LBH589, Valproic Acid (VPA), MS275 and Scriptaid in the patient-derived glioblastoma model. In more detail, SAHA and LBH589 were evaluated to determine predictors of response. Acetylated-histone-H3, γH2AX/53BP1, (p)Chek2/ATM, Bcl-2/Bcl-XL, p21(CIP1/WAF1) and caspase-3/7 were studied in relation to response. SAHA sensitized 50% of cultures, LBH589 45%, VPA and Scriptaid 40% and MS275 60%. Differences after treatment with SAHA/RTx or LBH589/RTx in a sensitive and resistant culture were increased acetylated-H3, caspase-3/7 and prolonged DNA damage repair γH2AX/53BP1 foci. pChek2 was found to be associated with both SAHA/RTx and LBH589/RTx response with a positive predictive value (PPV) of 90%. Bcl-XL had a PPV of 100% for LBH589/RTx response. Incubation with HDACi 24 and 48 hours pre-RTx resulted in the best efficacy of combination treatment. In conclusion a subset of patient-derived glioblastoma cultures were sensitive to HDACi/RTx. For SAHA and LBH589 responses were strongly associated with pChek2 and Bcl-XL, which warrant further clinical exploration. Additional information on responsiveness was obtained by DNA damage response markers and apoptosis related proteins 4).

Csordas, A. (1990) On the biological role of histone acetylation. Biochem. J. 265, 23-38
Riggs, M.G., Whittaker, R.G., Neumann, J.R., and Ingram, V.M. (1977) n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268, 462-464
Li S, Liu X, Chen X, Zhang L, Wang X. Histone deacetylase 6 promotes growth of glioblastoma through inhibition of SMAD2 signaling. Tumour Biol. 2015 Jul 7. [Epub ahead of print] PubMed PMID: 26150340.
Pont LM, Naipal K, Kloezeman JJ, Venkatesan S, van den Bent M, van Gent DC, Dirven CM, Kanaar R, Lamfers ML, Leenstra S. DNA damage response and anti-apoptotic proteins predict radiosensitization efficacy of HDAC inhibitors SAHA and LBH589 in patient-derived glioblastoma cells. Cancer Lett. 2015 Jan 28;356(2 Pt B):525-35. doi: 10.1016/j.canlet.2014.09.049. Epub 2014 Oct 8. PubMed PMID: 25305451.
histone_deacetylase.txt · Last modified: 2018/07/28 14:21 by administrador