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

• Published in: Oncotarget Vol. 8; no. 29; pp. 46856 - 46874
• Main Authors: Taniguchi, Hiroaki, Hoshino, Daisuke, Moriya, Chiharu, Zembutsu, Hitoshi, Nishiyama, Nobuhiro, Yamamoto, Hiroyuki, Kataoka, Kazunori, Imai, Kohzoh
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 18.07.2017
• Subjects: Adult; Aged; Animals; Biomarkers, Tumor; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cell Transformation, Neoplastic - genetics; Disease Models, Animal; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Lymphocytes, Tumor-Infiltrating - metabolism; Mice; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Organ Specificity; Phenotype; Repressor Proteins - genetics; Research Paper; RNA Interference; RNAi Therapeutics; Xenograft Model Antitumor Assays; Young Adult; PRDM14; epigenetic alterations; nucleic acid medicine; breast cancer stem cell; cancer stemness
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.16776

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.