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Research Article| Volume 63, ISSUE 2, P408-419, August 2015

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MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer

  • Author Footnotes
    † These authors contributed equally to this work.
    Hyun Jin Bae
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this work.
    Kwang Hwa Jung
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
    Search for articles by this author
  • Jung Woo Eun
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
    Search for articles by this author
  • Qingyu Shen
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
    Search for articles by this author
  • Hyung Seok Kim
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
    Search for articles by this author
  • Se Jin Park
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
    Search for articles by this author
  • Woo Chan Shin
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
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  • Hee Doo Yang
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
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  • Won Sang Park
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
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  • Jung Young Lee
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
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  • Suk Woo Nam
    Correspondence
    Corresponding author. Address: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Tel.: +82 2 2258 7314; fax: +82 2 537 6586.
    Affiliations
    Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea

    Cancer Evolution Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this work.
Published:March 26, 2015DOI:https://doi.org/10.1016/j.jhep.2015.03.019

      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

      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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