Open AccessHistone methylation‐mediated silencing of miR‐139 enhances invasion of non‐small‐cell lung cancer
Author(s) -
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
Publication year - 2015
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.505
Subject(s) - gene silencing , cancer research , biology , ectopic expression , microrna , dna methylation , cancer , metastasis , chromatin immunoprecipitation , lung cancer , gene expression , pathology , promoter , medicine , cell culture , gene , genetics
Micro RNA expression is frequently altered in human cancers, and some micro RNA s 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 NSCLC s. MiR‐139 is located within the intron of PDE 2A and its expression was significantly correlated with the expression of PDE 2A . A chromatin immunoprecipitation assay revealed that miR‐139 was epigenetically silenced by histone H3 lysine 27 trimethylation (H3K27me3) of its host gene PDE 2A and this process was independent of promoter DNA methylation. Pharmacological inhibition of both histone methylation and deacetylation‐induced miR‐139 with its host gene PDE 2A . 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 NSCLC s, 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 .