期刊
BRITISH JOURNAL OF CANCER
卷 112, 期 1, 页码 112-121出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2014.547
关键词
hepatocellular carcinoma (HCC); histone deacetylase inhibitor (HDACi); MICA; natural killer cells; microRNA; MCM7
类别
资金
- National 973 Basic Research Program of China [2013CB944901]
- Natural Science Foundation of China [81273220, 81472646, 31200651]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT13028]
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.
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