Histone Deacetylase Inhibitors Modulating Non-epigenetic Players: The Novel Mechanism for Small Molecule Based Therapeutic Intervention

被引:18
作者
Ganai, Shabir Ahmad [1 ]
机构
[1] Univ Kashmir, Dept Biotechnol, Epigenet & Chromatin Biol Lab, Srinagar 190006, Jammu & Kashmir, India
关键词
Acetylation; deacetylation; HATs; HDACs; HDACi; histone proteins; non-histone proteins; NF-KAPPA-B; PROSTATE-CANCER CELLS; HDAC INHIBITORS; DOWN-REGULATION; CYCLE ARREST; DNA-BINDING; ACETYLATION; ACTIVATION; APOPTOSIS; P53;
D O I
10.2174/1389450117666160527143257
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Histone deacetylases (HDACs) play a crucial role in regulating the expression and activity of myriad of proteins involved in tumour onset and progression. HDAC activity results in a nonpermissive chromatin conformation by erasing acetyl moiety from histone substrates culminating in transcriptional repression of those genes having significant role in tumourigenesis. Apart from histones, HDACs deacetylate a variety of non-histone proteins including transcription factors involved in controlling cell growth, differentiation and apoptosis. Histone deacetylase inhibitors (HDACi) are small-molecules restraining HDACs and hence modulating their biological activity. Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor-kappaB (NF-kappa B), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer. The present article explores the therapeutic role of HDACi with special emphasis on modulation of clinically relevant non-histone molecular targets. Extensive details regarding the non-histone proteins and their deregulation in disease states have also been provided. Moreover, the underlying molecular mechanism triggered by HDACi to overcome disease states by modulating the predefined targets has also been illuminated. The article strongly suggests the promising use of HDACi in therapeutic intervention against complications arising due to non-histone protein deregulation.
引用
收藏
页码:593 / 601
页数:9
相关论文
共 88 条
[11]   Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes [J].
Campuzano, V ;
Montermini, L ;
Lutz, Y ;
Cova, L ;
Hindelang, C ;
Jiralerspong, S ;
Trottier, Y ;
Kish, SJ ;
Faucheux, B ;
Trouillas, P ;
Authier, FJ ;
Durr, A ;
Mandel, JL ;
Vescovi, A ;
Pandolfo, M ;
Koenig, M .
HUMAN MOLECULAR GENETICS, 1997, 6 (11) :1771-1780
[12]   RETRACTED: Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation (Retracted article. See vol. 78, pg. 4097, 2018) [J].
Chen, Chang-Shi ;
Wang, Yu-Chieh ;
Yang, Hsiao-Ching ;
Huang, Po-Hsien ;
Kulp, Samuel K. ;
Yang, Chih-Cheng ;
Lu, Yen-Shen ;
Matsuyama, Shigemi ;
Chen, Ching-Yu ;
Chen, Ching-Shih .
CANCER RESEARCH, 2007, 67 (11) :5318-5327
[13]   Shaping the nuclear action of NF-κB [J].
Chen, LF ;
Greene, WC .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2004, 5 (05) :392-401
[14]   Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions [J].
Choudhary, Chunaram ;
Kumar, Chanchal ;
Gnad, Florian ;
Nielsen, Michael L. ;
Rehman, Michael ;
Walther, Tobias C. ;
Olsen, Jesper V. ;
Mann, Matthias .
SCIENCE, 2009, 325 (5942) :834-840
[15]   Multiple roles of HDAC inhibition in neurodegenerative conditions [J].
Chuang, De-Maw ;
Leng, Yan ;
Marinova, Zoya ;
Kim, Hyeon-Ju ;
Chiu, Chi-Tso .
TRENDS IN NEUROSCIENCES, 2009, 32 (11) :591-601
[16]   Histone deacetylase inhibitors in hematological malignancies and solid tumors [J].
Chun, Pusoon .
ARCHIVES OF PHARMACAL RESEARCH, 2015, 38 (06) :933-949
[17]   Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells [J].
Condorelli, F. ;
Gnemmi, I. ;
Vallario, A. ;
Genazzani, A. A. ;
Canonico, P. L. .
BRITISH JOURNAL OF PHARMACOLOGY, 2008, 153 (04) :657-668
[18]   Valosin-containing protein is a multiubiquitin chain targeting factor required in ubiquitin-proteasome degradation [J].
Dai, RM ;
Li, CCH .
NATURE CELL BIOLOGY, 2001, 3 (08) :740-744
[19]   Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-κB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-jun n-terminal kinase 1 activation [J].
Dai, Y ;
Rahmani, M ;
Dent, P ;
Grant, S .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (13) :5429-5444
[20]   Histone deacetylases (HDACs): characterization of the classical HDAC family [J].
De Ruijter, AJM ;
Van Gennip, AH ;
Caron, HN ;
Kemp, S ;
Van Kuilenburg, ABP .
BIOCHEMICAL JOURNAL, 2003, 370 :737-749