Abstract
Colorectal cancer pathogenesis remains incompletely understood. Here, we report that the heterochromatin protein HP1γ is upregulated commonly in human colorectal cancer, where it promotes cell proliferation in vitro and in vivo. Gene-expression and promoter-binding experiments demonstrated that HP1γ directly regulated CDKN1A (p21(Waf1/Cip1)) in a manner associated with methylation of histone H3K9 on its promoter. We identified miR-30a as a tumor-suppressive microRNA that targets HP1γ in vitro and in vivo to specifically suppress the growth of colorectal cancer in mouse xenograft models. MiR-30a was widely downregulated in primary human colorectal cancer tissues, where its expression correlated inversely with high levels of HP1γ protein. Our results identify a new miR-30a/HP1γ/p21 regulatory axis controlling colorectal cancer development, which may offer prognostic and therapeutic opportunities.
©2015 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / genetics
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / pathology*
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / pathology*
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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DNA Methylation
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Disease Progression
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Down-Regulation
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Gene Expression Regulation, Neoplastic
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HCT116 Cells
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HEK293 Cells
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Histones / genetics
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Histones / metabolism
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Humans
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Mice
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Mice, Nude
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MicroRNAs / genetics*
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Neoplasm Transplantation
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Promoter Regions, Genetic / genetics
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RNA Interference
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RNA, Small Interfering
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Transplantation, Heterologous
Substances
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CBX3 protein, human
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CDKN1A protein, human
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Chromosomal Proteins, Non-Histone
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Cyclin-Dependent Kinase Inhibitor p21
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Histones
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MIRN30b microRNA, human
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MicroRNAs
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RNA, Small Interfering