Dataset Information

Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization.

ABSTRACT:

Purpose

Histone deacetylase (HDAC) inhibitors radiosensitize tumor cells. To elucidate mechanisms underlying radiosensitization by HDAC inhibition, understanding of differential contributions of HDAC isotypes is needed. The aim of this study was to investigate involvement of known HDAC isotypes in modulation of cellular radiosensitivity.

Materials and methods

Because pharmacologic HDAC inhibitors lack isotype-specificity, RNA interference against 11 HDAC isotypes was used to inhibit HDAC in an isotype-specific manner. Radiation cell survival was evaluated using a clonogenic assay in SQ20B cells transfected with small interfering RNA specifically targeting HDAC isotypes. Immunocytochemistry was performed for detection of ?H2AX foci. Protein expression was measured using Western blotting.

Results

Among 11 HDAC isotypes tested, specific inhibition of 7 isotypes (HDAC1, HDAC3, HDAC4, HDAC6, HDAC7, HDAC10, and HDAC11) enhanced radiation lethality in SQ20B cells. Radiosensitization by inhibition of these HDAC isotypes was accompanied by delay of DNA double strand break repair. Radiosensitivity of SQ20B cells was not altered by selective inhibition of the remaining four isotypes (HDAC2, HDAC5, HDAC8, and HDAC9). Inhibition of HDAC isotypes resulted in downregulation of various proteins involved in pro-survival and DNA damage repair pathways.

Conclusion

Isotype-specificity exists in HDAC inhibition-induced radiosensitization. Different HDAC isotypes are differentially involved in modulation of cellular radiosensitivity.

SUBMITTER: Kim JH

PROVIDER: S-EPMC4946349 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization.

Kim Jin Ho JH Moon Sung Ho SH No Mina M Kim Jae Jin JJ Choi Eun Jung EJ Cho Bong Jun BJ Kim Jae Sung JS Kim Il Han IH Kim In Ah IA

Cancer research and treatment 20151117 3

<h4>Purpose</h4>Histone deacetylase (HDAC) inhibitors radiosensitize tumor cells. To elucidate mechanisms underlying radiosensitization by HDAC inhibition, understanding of differential contributions of HDAC isotypes is needed. The aim of this study was to investigate involvement of known HDAC isotypes in modulation of cellular radiosensitivity.<h4>Materials and methods</h4>Because pharmacologic HDAC inhibitors lack isotype-specificity, RNA interference against 11 HDAC isotypes was used to inhib ...[more]

PMID: 26582395

Similar Datasets

Project description:The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several "off label" indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact that certain types of neuropathic pain, in particular complex regional pain syndrome, demonstrate a proliferative nature, with the capacity to spread from an injured limb, for example, to a non-injured limb and perhaps to essentially the entire body. Sensory neuronal sprouting in the spinal cord has been observed under conditions where there is a high sensory input from painful stimuli. Searches of gene expression signatures in the BroadBuild02 Molecular Signature Database using their connectivity map software suggested that phenoxybenzamine may have histone deacetylase inhibitory activity. Studies by others have reported inhibitory effects of phenoxybenzamine on growth, invasion and migration of human tumor cell cultures and, in one study, inhibition of tumor expansion in animal experiments. Inhibitory effects on human tumor cell cultures are also reported in the present study. Phenoxybenzamine was also found to have histone deacetylase inhibitory activity; histone deacetylase isoforms 5, 6, and 9 were the most sensitive to inhibition by phenoxybenzamine. The importance of elevated levels of these isoforms as biomarkers of poor prognosis in human malignant disease, and the recognized suppression of tumor growth that may accrue from their inhibition, opens consideration of possible translation of phenoxybenzamine to new clinical applications. This might be facilitated by the fact that phenoxybenzamine is already an approved drug entity. There appears to be no previous report of the activity of phenoxybenzamine as a histone deacetylase inhibitor.

Dataset Information

Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization.

Purpose

Materials and methods

Results

Conclusion

Publications

Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization.

Similar Datasets

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