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

Cancer Medicine

Kousuke Watanabe³  Yosuke Amano³  Rie Ishikawa³  Mitsuhiro Sunohara³  Hidenori Kage³  Junji Ichinose²  Atsushi Sano²  Jun Nakajima²  Masashi Fukayama⁴  Yutaka Yatomi¹  Takahide Nagase³  Nobuya Ohishi³ 

[1] Department of Clinical Laboratory, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan;Department of Cardiothoracic Surgery, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan;Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan;Department of Pathology, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan

关键词: Epigenetic repression;    histones;    lung neoplasms;    microRNAs;    neoplasm metastasis;   

DOI  :  10.1002/cam4.505

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY   
© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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