Histone methylation‐mediated silencing of miR‐139 enhances invasion of non‐small‐cell lung cancer

MicroRNA expression is frequently altered in human cancers, and some microRNAs act as oncogenes or tumor suppressors. MiR‐139‐5p (denoted thereafter as miR‐139) has recently been reported to function as a tumor suppressor in several types of human cancer (hepatocellular carcinoma, colorectal cancer,...

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Published in:Cancer medicine (Malden, MA) MA), 2015-10, Vol.4 (10), p.1573-1582
Main Authors: Watanabe, Kousuke, Amano, Yosuke, Ishikawa, Rie, Sunohara, Mitsuhiro, Kage, Hidenori, Ichinose, Junji, Sano, Atsushi, Nakajima, Jun, Fukayama, Masashi, Yatomi, Yutaka, Nagase, Takahide, Ohishi, Nobuya, Takai, Daiya
Format: Article
Language:English
Subjects:
Breast cancer
Cancer Biology
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Cell cycle
Cell Line, Tumor
Chromatin
Colorectal cancer
Colorectal carcinoma
Cyclic Nucleotide Phosphodiesterases, Type 2 - genetics
Deacetylation
Deoxyribonucleic acid
DNA
DNA methylation
DNA Methylation - drug effects
DNA Methylation - genetics
Ectopic expression
Ectopic Gene Expression
Epigenetic repression
Epigenetics
Esophagus
Extracellular matrix
Female
Gastric cancer
Gene expression
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Tumor Suppressor
Genomes
Genotype & phenotype
Hepatocellular carcinoma
Histone H3
histones
Histones - drug effects
Histones - genetics
Humans
Immunoprecipitation
Invasiveness
Kinases
Liver cancer
Lung cancer
lung neoplasms
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Lymph nodes
Lymphatic Metastasis
Lymphatic system
Lysine
Male
Metastases
Metastasis
MicroRNAs
MicroRNAs - genetics
miRNA
Neoplasm Invasiveness - genetics
neoplasm metastasis
Non-small cell lung carcinoma
Phenols
Phenotypes
Promoter Regions, Genetic
Tumor cell lines
Tumor suppressor genes
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Summary:MicroRNA expression is frequently altered in human cancers, and some microRNAs act as oncogenes or tumor suppressors. MiR‐139‐5p (denoted thereafter as miR‐139) has recently been reported to function as a tumor suppressor in several types of human cancer (hepatocellular carcinoma, colorectal cancer, breast cancer, and gastric cancer), but its function in non‐small‐cell lung cancer (NSCLC) and the mechanism of its suppression have not been studied in detail. MiR‐139 was suppressed frequently in primary NSCLCs. MiR‐139 is located within the intron of PDE2A and its expression was significantly correlated with the expression of PDE2A. A chromatin immunoprecipitation assay revealed that miR‐139 was epigenetically silenced by histone H3 lysine 27 trimethylation (H3K27me3) of its host gene PDE2A and this process was independent of promoter DNA methylation. Pharmacological inhibition of both histone methylation and deacetylation‐induced miR‐139 with its host gene PDE2A. Ectopic expression of miR‐139 in lung cancer cell lines did not affect the proliferation nor the migration but significantly suppressed the invasion through the extracellular matrix. In primary NSCLCs, decreased expression of miR‐139 was significantly associated with distant lymph node metastasis and histological invasiveness (lymphatic invasion and vascular invasion) on both univariate and multivariate analyses. Collectively, these results suggest that H3K27me3‐mediated silencing of miR‐139 enhances an invasive and metastatic phenotype of NSCLC. miR‐139 was epigenetically silenced with its host gene PDE2A by histone H3 lysine 27 trimethylation (H3K27me3) in non‐small‐cell lung cancer. Ectopic expression of miR‐139 suppressed the invasion of lung cancer cells. Our results suggest that H3K27me3‐mediated silencing of miR‐139 may play a role in lung cancer metastasis.
ISSN:2045-7634
2045-7634
DOI:10.1002/cam4.505