Abstract
In the present study, we found that selective inhibition of histone deacetylase 2 (HDAC2) with small inhibitory RNA (siRNA) induced survivin downregulation in a p53-dependent manner. Interestingly, suberoylanilide hydroxamic acid (SAHA) or knockdown of HDAC2 induced downregulation of Mdm2, a negative regulator of p53, at the protein level. SAHA and/or HDAC2 siRNA increased Mdm2 ubiquitination, and MG132, an inhibitor of proteosome function, prevented HDAC2 inhibition-induced degradation of Mdm2. Clinically, the mRNA levels of HDAC2 and survivin were prominently overexpressed in lung cancer patients compared to normal lung tissues. Silencing of HDAC2 enhanced the cell death caused by ionizing radiation in lung cancer cells. Collectively, our results indicate that selective inhibition of HDAC2 causes survivin downregulation through activation of p53, which is mediated by downregulation of Mdm2. They further suggest that HDAC2 may exert a dominant effect on lung cancer cell survival by sustaining Mdm2-survivin levels.
Highlights
Members of the histone deacetylase (HDAC) family, encoded by 18 distinct genes, are divided into four classes—class I, class IIa, class IIb, class III and class IV—based on their homology
To further investigate whether p53 is associated with Suberoylanilide hydroxamic acid (SAHA)-induced downregulation of survivin, we examined survivin expression in p53 wild-type A549 cells and p53-null H1299 cells after treatment with SAHA
In H1299 cells transfected with a p53 expression plasmid, SAHA treatment resulted in downregulation of survivin (Fig. 1E)
Summary
Members of the histone deacetylase (HDAC) family, encoded by 18 distinct genes, are divided into four classes—class I, class IIa, class IIb, class III and class IV—based on their homology. In addition to interacting with chromatin proteins, HDACs can lead to altered expression of a large number of genes through direct interaction with non-histone proteins, such as the transcription factors E2F and Stat, and the tumor-suppressor p53 [3, 4]. Several www.impactjournals.com/oncotarget studies have shown that class I and II HDACs (HDAC110) are overexpressed in some cancers, including gastric cancer, colorectal cancer, prostate cancer, and lung cancer [5, 6]. Both altered expression and mutation of HDACs have been linked to cancer formation and progression, reflecting the fact that these changes in HDACs induce aberrant transcription of key genes that regulate important cellular functions [2]. HDAC inhibitors have been evaluated in clinical trials, the different and specific roles of individual HDACs in carcinogenesis remain unclear
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