Promotion of Anchorage-independent Growth by Cytoplasmic and Nuclear Histone Deacetylase 9

Abstract

Genetic mutation is a trigger for the generation of malignant cells and an aberrant epigenetic status contributes to the maintenance of mutations and proliferation of mutated cells. Along with DNA methylation, histone modifications such as acetylation and methylation are significant to biological processes. Histone deacetylases (HDACs) are important epigenetic regulators of chromatin modifications and gene expression. Though several HDAC inhibitors are currently being tested in clinical trials, the roles of HDACs in malignant transformation remain unknown. Here, we showed that the expression of two forms of Hdac9, a full-length version (Hdac9FL) and a splicing variant lacking exon 7 (Hdac9Δ7), both class IIa HDACs, was up-regulated during chemically induced hepatocarcinogenesis. In addition, we found that HDAC9FL and HDAC9Δ7 are located in the nucleus and cytoplasm, respectively. We also found their nuclear localization and nuclear export signals to be encoded in exon 7 and exon 25, respectively. Though the two isoforms could not transform mouse NIH-3T3 fibroblasts, they promoted tumor cell anchorage-independent growth on soft agarose. The HDAC9 variants do not seem to cause cell transformation, but cytoplasmic and nuclear HDAC9 may contribute to the survival of malignant cells in the early stages of hepatocarcinogenesis.