Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1

Abstract

Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

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.…”

Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform-Selective Inhibitors

“…[5][6][7][8][9][10][11] Primary HDAC antibodies recognizing each of the isoforms were immobilized to different wells of a plate, followed by incubation with HeLa cell lysates to affix the respective HDAC isoform (Fig. 2).…”

“…As illustrative examples, increased expression of HDAC1 was observed in gastric, 5 colon, 6 prostrate, 7 and breast cancer, 8 while HDAC2 was overexpressed in gastric 9 and colorectal cancer. 10 Among the class II proteins, HDAC6 is overexpressed in oral squamous cell carcinoma and breast cancer tumors. 11 Unlike other HDAC isoforms, HDAC6 plays important roles in multiple cancer-relevant biological processes that are not epigenetic in nature.…”

Antibody response to a non‐conserved C‐terminal part of human histone deacetylase 3 in colon cancer patients

“…11,12 In colon cancer we found that the protein levels of HDAC1, HDAC2 and HDAC3, but not their mRNA levels, were increased in tumors as compared to non-cancerous colon mucosa from the same patients. Of note, overexpression of HDAC1 and HDAC2 in colorectal tumors was reported recently by Huang et al, 29 who used alternative techniques to estimate mRNA and protein levels (quantitative real-time RT-PCR and immunohistochemistry, respectively).…”