Introduction An imbalance between the acetylation and deacetylation of histone proteins regulated
by histone deacetylases (HDACs) has been shown in different types of cancer including
hepatocellular carcinoma (HCC). HDAC inhibition appears as promising therapeutic strategy
for HCC. However, mostly unspecific HDAC inhibitiors have been applied and the knowledge
about the expression and role of individual HDACs in HCC is very limited.
The aim of the study was to unveil the expression and function of HDAC7 in HCC.
Methods and Results HDAC7 expression was significantly increased in 4 human HCC cell lines (Hep3B, HepG2,
PLC, Huh7) compared to primary human hepatocytes (PHH). Furthermore, HDAC7 expression
in a spontaneous murine HCC model and human HCC specimens compared to non-tumorous
liver tissue were significantly increased. TCGA (The Cancer Genome Atlas) data set
analysis revealed a significant correlation between high HDAC7 expression and poor
patients’ survival. Interestingly, in silico analysis applying the GEPIA-platform
showed that HDAC7 expression in human HCC tissues correlates significantly with the
expression of genes regulated by hypoxia such as GLUT1 and VEGF. In line with this,
hypoxia significantly increased HDAC7 expression in human HCC cells in vitro. Further
in vitro studies showed that siRNA mediated depletion of HDAC7 significantly reduced
NFkB-activity in HCC cells. Furthermore, we found increased p62 and LC3 II protein
levels in HDAC7-depleted cells indicating an impairment of the autophagic flux.
Summary and Conclusion Our study indicates HDAC7 as strong pro-tumorigenic factor in HCC and newly identifies
hypoxia, a condition frequently occurring in HCC, as promotor of HDAC7 expression
in HCC. These data indicate HDAC7 expression as prognostic marker and suggest specific
HDAC7 inhibition as promising therapeutic strategy in HCC.
