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.
Subject(s)
Cell Transformation, Neoplastic/pathology , Chromosomal Proteins, Non-Histone/metabolism , Colorectal Neoplasms/pathology , Cyclin-Dependent Kinase Inhibitor p21/metabolism , MicroRNAs/genetics , Animals , Cell Line, Tumor , Cell Proliferation/genetics , Cell Transformation, Neoplastic/genetics , Chromosomal Proteins, Non-Histone/genetics , Colorectal Neoplasms/genetics , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , DNA Methylation , Disease Progression , Down-Regulation , Gene Expression Regulation, Neoplastic , HCT116 Cells , HEK293 Cells , Histones/genetics , Histones/metabolism , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Promoter Regions, Genetic/genetics , RNA Interference , RNA, Small Interfering , Transplantation, HeterologousABSTRACT
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. However, the molecular mechanisms of CRC pathogenesis are not fully understood. In this study, we report the characterization of LYAR (Ly-1 antibody reactive clone) as a key regulator of the migration and invasion of human CRC cells. Immunohistochemistry analysis demonstrated that LYAR is expressed at a higher level in metastatic CRC tissues. We found that LYAR promoted the migratory and invasive capabilities of CRC cells. Gene expression profile analysis of CRC cells showed that LGALS1, which encodes the galectin-1 protein, was a potential target of LYAR. The ChIP assay and gene reporter assays indicated that LYAR directly bound to the LGALS1 promoter. The ectopic expression of galectin-1 partially restored the mobile potential of LYAR knocked-down cells, which suggests that galectin-1 contributed to the LYAR-promoted cell migration and invasion of CRC cells. Thus, this study revealed a novel mechanism by which the transcription factor LYAR may promote tumor cell migration and invasion by upregulating galectin-1 gene expression in CRC.
