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

Authors :
Jin Ho Kim
Sung Ho Moon
Mina No
Jae Jin Kim
Eun Jung Choi
Bong Jun Cho
Jae Sung Kim
Il Han Kim
In Ah Kim
Source :
Cancer Research & Treatment; 2016, Vol. 48 Issue 3, p1130-1140, 11p
Publication Year :
2016

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 yH2AX 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15982998
Volume :
48
Issue :
3
Database :
Complementary Index
Journal :
Cancer Research & Treatment
Publication Type :
Academic Journal
Accession number :
117047308
Full Text :
https://doi.org/10.4143/crt.2015.206