Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma.
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.
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
H
H
Yang
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
P
P
Lan
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
Z
Z
Hou
Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
Y
Y
Guan
1] Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China [2] Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
J
J
Zhang
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
W
W
Xu
Department of Microbiology and Immunology, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China.
Z
Z
Tian
1] Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China [2] Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
C
C
Zhang
D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D057890:Epigenomics; D056945:Hep G2 Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D064168:Minichromosome Maintenance Complex Component 7 / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C099187:MHC class I-related chain A; C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D000077337:Vorinostat; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7