Role for Histone Deacetylase 1 in Human Tumor Cell Proliferation

Abstract

Posttranslational modifications of core histones are central to the regulation of gene expression. Histone deacetylases (HDACs) repress transcription by deacetylating histones, and class I HDACs have a crucial role in mouse, Xenopus laevis, zebra fish, and Caenorhabditis elegans development. The role of individual class I HDACs in tumor cell proliferation was investigated using RNA interference-mediated protein knockdown. We show here that in the absence of HDAC1 cells can arrest either at the G 1 phase of the cell cycle or at the G 2 /M transition, resulting in the loss of mitotic cells, cell growth inhibition, and an increase in the percentage of apoptotic cells. On the contrary, HDAC2 knockdown showed no effect on cell proliferation unless we concurrently knocked down HDAC1. Using gene expression profiling analysis, we found that inactivation of HDAC1 affected the transcription of specific target genes involved in proliferation and apoptosis. Furthermore, HDAC2 downregulation did not cause significant changes compared to control cells, while inactivation of HDAC1, HDAC1 plus HDAC2, or HDAC3 resulted in more distinct clusters. Loss of these HDACs might impair cell cycle progression by affecting not only the transcription of specific target genes but also other biological processes. Our data support the idea that a drug targeting specific HDACs could be highly beneficial in the treatment of cancer.

The Histone Acetyltransferase TIP60 Interacts with c-Myb and Inactivates Its Transcriptional Activity in Human Leukemia

“…Last, we tested whether HDAC1/2 knockdown affects c-Myc expression in K562 cells. Consistent with a previous report (25), c-Myc expression increased upon loss of either HDAC1 or HDAC2 but not HDAC3 (Fig. 6E).…”

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

“…Previous reports demonstrated that class I HDACs are recruited by Sp1 to the p21 WAF1/Cip1 promoter (Lagger et al, 2002;Huang et al, 2005;Wilson et al, 2006;Senese et al, 2007;Spurling et al, 2008). Our findings identify HDAC4 as a new component of the Sp1-dependent repressor complex on the p21 WAF1/Cip1 promoter.…”

“…However, most HDAC inhibitors are global and nonspecific for the various HDAC isoforms. Class I HDACs regulate p21 WAF1/Cip1 gene expression (Huang et al, 2005(Huang et al, , 2006Wilson et al, 2006;Senese et al, 2007;Spurling et al, 2008), but it is not known whether other HDACs are involved.…”

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

“…siRNA studies have been crucial to understanding the importance of individual isoforms of class I HDACs and have helped characterize their function in proliferation and tumorigenesis (Wilson et al, 2006;Spurling et al, 2008;Weichert et al, 2008b), including HDAC-1 (Glaser et al, 2003;Inoue et al, 2006;Senese et al, 2007). In this study, we report that knockdown of HDAC-1, either by miR-449a or synthetic HDAC-1 siRNA, results in cell-cycle arrest, a senescent-like phenotype and loss of clonogenicity in PC-3 cells.…”