Abstract
Simple SummaryHistone deacetylases (HDACs) are known to play a role in malignant transformation of cancer cells, however, the critical HDAC responsible for the dedifferentiation of hepatocellular carcinoma (HCC) cells remains unclear. The aim of our study was to identify the HDAC related to the dedifferentiation of HCC. We confirmed preferential expression of HDAC9, a class II HDAC, in undifferentiated hepatoma cells and a positive correlation of gene expression between HDAC9 and dedifferentiation markers by database analysis of HCC patients. Genetic and pharmacological inhibition of HDAC9 showed decreased cell proliferation and sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. HDAC9 suppression showed significant down-regulation of aldehyde dehydrogenase 1A3 (ALDH1A3), a stemness-related gene reported in several malignancies including HCC. We also confirmed that ALDH activity is required for the anchorage-independent cell growth of undifferentiated HCC cells. Inhibition of HDAC9 may be a therapeutic strategy for targeting dedifferentiated HCC cells with stemness features.Aberrant activation of histone deacetylases (HDACs) is one of the causes of tumor cell transformation in many types of cancer, however, the critical HDAC responsible for the malignant transformation remain unclear. To identify the HDAC related to the dedifferentiation of hepatocellular carcinoma (HCC) cells, we investigated the expression profile of HDACs in differentiated and undifferentiated hepatoma cells. We found that HDAC9, a member of the class II HDAC, is preferentially expressed in undifferentiated HCC cells. Analysis of 373 HCC patients in The Cancer Genome Atlas (TCGA) database revealed that the expression of HDAC9 mRNA positively correlated with the markers of mesenchymal phenotype and stemness, and conversely, negatively correlated with hepatic differentiation markers. HDAC9 was transcriptionally upregulated in epithelial–mesenchymal transition (EMT)-induced HCC cells treated with TGF-β. Genetic and pharmacological inhibition of HDAC9 in undifferentiated HCC cells showed decreased sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. We also showed that aldehyde dehydrogenase 1A3 (ALDH1A3) was downregulated in HDAC9-suppressing cells, and ALDH inhibitor disulfiram significantly decreased the sphere formation of undifferentiated HCC cells. Together, our data provide useful information for the development of HDAC9-specific inhibitors for the treatment of HCC progression.
Highlights
Histone acetylation and deacetylation are known epigenetic modifications, which can play a role in a gene regulation
To determine which histone deacetylases (HDACs) is involved in the dedifferentiation of hepatocellular carcinoma (HCC) cells, a gene expression analysis of class I, class II, and class IV HDAC genes was performed on a panel of hepatoma cells including two differentiated (HepG2 and HuH1) and two undifferentiated (HLE and HLF) types of HCC
Quantitative PCR experiments revealed for HDAC1, HDAC2, HDAC3, HDAC8, and HDAC9 genes, while the other HDACs (HDAC4, that a measurable expression of class were observed in all cell lines examined (Figure 1a)
Summary
Histone acetylation and deacetylation are known epigenetic modifications, which can play a role in a gene regulation. Small molecules that block the enzymatic activity of HDACs (HDAC inhibitors), such as tricostatin A, valproic acid, romidepsin, and vorinostat, have been approved or are under investigation for the promising cancer treatment. These agents have possible side effects caused by inhibition of a broad range of HDACs [3]. It is important to identify which HDAC plays a pivotal role in the malignant transformation of cancer cells of the target organ
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