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Silencing PRDM14 expression by an innovative RNAi therapy inhibits stemness, tumorigenicity, and metastasis of breast cancer.

Abstract

PR domain zinc finger protein 14 (PRDM14) maintains stemness in embryonic stem cells via epigenetic mechanisms. Although PRDM14 is elevated in several cancers, it is unclear if and how PRDM14 confers stem cell-like properties and epigenetic changes to cancer cells. Here, we examined the phenotypic characteristics and epigenetic and gene expression profiles of cancer cells that differentially express PRDM14, and assessed the potential of PRDM14-targeted cancer therapy. PRDM14 expression was markedly increased in many different cancer types and correlated with poor survival of breast cancer patients. PRDM14 conferred stem cell-like phenotypes to cancer cells and regulated the expression of genes involved in cancer stemness, metastasis, and chemoresistance. PRDM14 also reduced the methylation of proto-oncogene and stemness gene promoters and PRDM14-binding regions were primarily occupied by histone H3 Lys-4 trimethylation (H3K4me3), both of which are positively correlated with gene expression. Moreover, strong PRDM14 binding sites coincided with promoters containing both H3K4me3 and H3K27me3 histone marks. Using calcium phosphate hybrid micelles as an RNAi delivery system, silencing of PRDM14 expression by chimera RNAi reduced tumor size and metastasis in vivo without causing adverse effects. Conditional loss of PRDM14 function also improved survival of MMTV-Wnt-1 transgenic mice, a spontaneous model of murine breast cancer. Our findings suggest that PRDM14 inhibition may be an effective and novel therapy for cancer stem cells.

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  • Authors+Show Affiliations

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    The Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

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    Cancer Biology Department, The Kanagawa Cancer Center Research Institute, Kanagawa 241-0815, Japan.

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    The Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

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    Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

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    Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Kanagawa 226-8503, Japan.

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    Department of Gastroenterology and Hepatology, School of Medicine, St. Marianna Medical University, Kanagawa 216-0015, Japan.

    ,

    Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan.

    The Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

    Source

    Oncotarget : 2017 Apr 01 pg

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28423353