Background & Aims
Most common reason behind changes in histone deacetylase (HDAC) function is its overexpression
in cancer. However, among HDACs in liver cancer, HDAC6 is uniquely endowed with a
tumor suppressor, but the mechanism underlying HDAC6 inactivation has yet to be uncovered.
Methods
Microarray profiling and target prediction programs were used to identify miRNAs targeting
HDAC6. A series of inhibitors, activators and siRNAs was introduced to validate regulatory
mechanisms for microRNA-221-3p (miR-221) governing HDAC6 in hepatocarcinogenesis.
Results
Comprehensive miRNA profiling analysis identified seven putative endogenous miRNAs
that are significantly upregulated in hepatocellular carcinoma (HCC). While miR-221
was identified as a suppressor of HDAC6 by ectopic expression of miRNA mimics in Dicer knockdown cells, targeted-disruption of miR-221 repressed cancer cell growth through
derepressing HDAC6 expression. Suppression of HDAC6 via miR-221 was induced by JNK/c-Jun
signaling in liver cancer cells but not in normal hepatic cells. Additionally, cytokine-induced
NF-κBp65 independently regulated miR-221, thereby suppressing HDAC6 expression in
HCC cells. HCC tissues derived from chemical-induced rat and H-ras12V transgenic mice liver cancer models validated that JNK/c-Jun activation and NF-κBp65
nuclear translocation are essential for the transcription of miR-221 leading to repression
of HDAC6 in HCC.
Conclusions
Our findings suggest that the functional loss or suppression of the tumor suppressor
HDAC6 is caused by induction of miR-221 through coordinated JNK/c-Jun- and NF-κB-signaling
pathways during liver tumorigenesis, providing a novel target for the molecular treatment
of liver malignancies.
Graphical abstract
Graphical Abstract
Abbreviations:
HCC (hepatocellular carcinoma), HDAC6 (histone deacetylases 6), miRNA (microRNA), 5-aza (5-aza-2′-deoxycytidine), TSA (trichostatin A), GAPDH (glyceraldehyde-3-phosphate dehydrogenase), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), UTR (untranslated region), ChIP (Chromatin Immunoprecipitation), HGF (hepatocyte growth factor), qRT-PCR (quantitative real-time polymerase chain reaction)Keywords
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Article info
Publication history
Published online: March 26, 2015
Accepted:
March 16,
2015
Received in revised form:
March 4,
2015
Received:
August 8,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
