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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."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.org/dc/terms/identifier"doi:10.1016/j.jhep.2015.03.019"xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Kim H.S."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Shen Q."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Park S.J."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Lee J.Y."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Jung K.H."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Nam S.W."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Park W.S."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Bae H.J."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Yang H.D."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Shin W.C."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/author"Eun J.W."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/name"J Hepatol"xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/pages"408-419"xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/title"MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer."xsd:string
http://purl.uniprot.org/citations/25817558http://purl.uniprot.org/core/volume"63"xsd:string
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