Targeting histone deacetylase in cancer therapy.
Histone deacetylase (HDAC) is recognized as one of the promising targets for cancer treatment as many HDAC inhibitors have entered clinical trials for both solid and liquid tumors. Nevertheless, the mechanisms underlying the antiproliferative effects of HDAC inhibitors remain elusive. Although they have been shown to regulate the transcription of a defined set of genes through chromatin remodeling, increasing evidence suggests that modifications of the epigenetic histone code may not be the primary mechanism for HDAC inhibitor-mediated growth inhibition and apoptosis in cancer cells. While histones still represent a primary target for the physiological function of HDACs, the antitumor effect of HDAC inhibitors might also be attributed to transcription-independent mechanisms by modulating the acetylation status of a series of nonhistone targets. Also noteworthy is the effect of HDAC inhibitors on Akt downregulation through the alteration of protein phosphatase 1 (PP1) complex formation. To provide an overview of the use of HDAC inhibitors in cancer treatment, this review addresses the following subjects: (1) the physiological relevance of HDAC-mediated acetylation of histone and nonhistone substrates, (2) the chemical biology of HDACs and development of a novel class of HDAC inhibitors, and (3) the protein acetylation-independent effect of HDAC inhibitors on the activation status of signaling kinases.
Lin
Hsiang-Yu
HY
Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
Chen
Chang-Shi
CS
Lin
Shuan-Pei
SP
Weng
Jing-Ru
JR
Chen
Ching-Shih
CS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009369:Neoplasms / Q000201:enzymology* / Q000628:therapy*; D011487:Protein Conformation; D015398:Signal Transduction
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008024:Ligands