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Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma
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Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma
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Journal Article
Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma
2015
Overview
Background:
Epigenetic therapy using histone deacetylase inhibitors (HDACi) has shown promise in clinical trials for the treatment of human malignancies. In addition to the immediate effects on the tumour cell growth, HDACi upregulates the expression of MHC class I-related chain molecules A and B (MICA and MICB), resulting in an enhanced susceptibility of tumour cells to natural killer cell-mediated lysis. The molecular mechanism underlying is still unclear.
Methods:
The transcriptional regulation mechanism underlying suberoylanilide hydroxamic acid (SAHA)-mediated regulation of MICA and related miRNA expression was investigated using promoter acetylation assays, bioinformatics analysis and chromatin immunoprecipitation assay.
Results:
SAHA upregulates the transcription of
MICA/B
by promoting MICA-associated histone acetylation while suppressing the MICA/B-targeting miRNAs miR-20a, miR-93 and miR-106b. The mechanism by which SAHA repressed miRNAs transcription involved repression of their host genes (
miR-17-92
cluster and
MCM7
). SAHA downregulated the
miR-17-92
cluster by abolishing tyrosine phosphorylation of STAT3 and decreased
MCM7
transcription through localised histone deacetylation.
Conclusions:
The HDACi SAHA epigenetically upregulates MICA expression through regulating the expression of
miR-17-92
cluster and
MCM7
in hepatoma, thus enhancing the sensitivity of HCC to natural killer cell-mediated lysis. This novel mechanism of action provides promise for HDACi in therapy of HCC.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biomedical and Life Sciences
/ Carcinoma, Hepatocellular - drug therapy
/ Carcinoma, Hepatocellular - genetics
/ Carcinoma, Hepatocellular - metabolism
/ Down-Regulation - drug effects
/ Histocompatibility Antigens Class I - biosynthesis
/ Histocompatibility Antigens Class I - genetics
/ Histone Deacetylase Inhibitors - pharmacology
/ Humans
/ Hydroxamic Acids - pharmacology
/ Liver Neoplasms - drug therapy
/ Liver Neoplasms - metabolism
/ Minichromosome Maintenance Complex Component 7 - genetics
/ Minichromosome Maintenance Complex Component 7 - metabolism
/ Oncology
