JARID2 is involved in transforming growth factor-beta-induced epithelial-mesenchymal transition of lung and colon cancer cell lines.

Shoichiro Tange,Minoru Terashima,Akihiko Ishimura,Takeshi Suzuki,Dulamsuren Oktyabri,Jung Weon Lee

doi:10.1371/journal.pone.0115684

Abstract

Histone methylation plays a crucial role in various biological and pathological processes including cancer development. In this study, we discovered that JARID2, an interacting component of Polycomb repressive complex-2 (PRC2) that catalyzes methylation of lysine 27 of histone H3 (H3K27), was involved in Transforming Growth Factor-beta (TGF-ß)-induced epithelial-mesenchymal transition (EMT) of A549 lung cancer cell line and HT29 colon cancer cell line. The expression of JARID2 was increased during TGF-ß-induced EMT of these cell lines and knockdown of JARID2 inhibited TGF-ß-induced morphological conversion of the cells associated with EMT. JARID2 knockdown itself had no effect in the expression of EMT-related genes but antagonized TGF-ß-dependent expression changes of EMT-related genes such as CDH1, ZEB family and microRNA-200 family. Chromatin immunoprecipitation assays showed that JARID2 was implicated in TGF-ß-induced transcriptional repression of CDH1 and microRNA-200 family genes through the regulation of histone H3 methylation and EZH2 occupancies on their regulatory regions. Our study demonstrated a novel role of JARID2 protein, which may control PRC2 recruitment and histone methylation during TGF-ß-induced EMT of lung and colon cancer cell lines.

Highlights

Lysine (K) methylation on the amino-terminal tail of histone H3 (K4, K9, K27 and K36) has emerged as an important post-translational modification due to its specific dynamics for transcriptional regulation [1, 2]
We found that knockdown of JARID2 antagonized TGF-ß-induced epithelialmesenchymal transition (EMT) of A549 lung cancer cell line and HT29 colon cancer cell line by inhibiting TGF-ß-dependent changes in expression of EMT-related genes such as CDH1, ZEB family and miR-200 family
Chromatin immunoprecipitation (ChIP) analyses revealed that JARID2 might induce the increase of EZH2 recruitment and histone H3K27 methylation on the regulatory regions of CDH1 and miR-200 family genes in the presence of TGF-ß, thereby causing TGF-ßdependent transcriptional repression

Summary

Introduction

Lysine (K) methylation on the amino-terminal tail of histone H3 (K4, K9, K27 and K36) has emerged as an important post-translational modification due to its specific dynamics for transcriptional regulation [1, 2]. Methylation of H3K4 has been tightly linked to active transcription whereas methylation of H3K9 and H3K27 are repressive marks of chromatin. These modifications are regulated by histone lysine methyltransferases (KMTs) and lysine demethylases (KDMs). In order to find novel genes implicated in cancer development, we have performed retroviral insertional mutagenesis in mice. This screen led to the isolation of hundreds of candidate cancer genes including many genes encoding KMTs and KDMs [4, 5]. Our studies revealed that histone methyl-modifying enzymes were involved in tumor initiation and in tumor progression

Methods

Results

Conclusion