Targeting Protein Arginine Methyltransferase 5 Inhibits Colorectal Cancer Growth by Decreasing Arginine Methylation of EIF4E and FGFR3

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Jun 17

PMID 26078354

Citations 52

Authors

Baolai Zhang

Shuhong Dong

Ruiming Zhu

Chunyan Hu

Jing Hou

Yan Li

Qian Zhao

Xue Shao

Qian Bu

Hongyu Li

Yongjie Wu

Xiaobo Cen

Yinglan Zhao

Affiliations

Soon will be listed here.

Abstract

Protein arginine methyltransferases (PRMTs) plays critical roles in cancer. PRMT5 has been implicated in several types of tumors. However, the role of PRMT5 in cancer development remains to be fully elucidated. Here, we provide evidence that PRMT5 is overexpressed in colorectal cancer (CRC) cells and patient-derived primary tumors, correlated with increased cell growth and decreased overall patient survival. Arginine methyltransferase inhibitor 1 (AMI-1)strongly inhibited tumor growth, increased the ratio of Bax/Bcl-2, and induced apoptosis in mouse CRC xenograt model. AMI-1 also induced apoptosis and decreased the migratory activity in several CRC cells. In CRC xenografts AMI-1 significantly decreased symmetric dimethylation of histone 4 (H4R3me2s), a histone mark of type II PRMT5, but not the expression of H4R3me2a, a histone mark of type I PRMTs. These results suggest that the inhibition of PRMT5 contributes to the antitumor efficacy of AMI-1. Chromatin immunoprecipitation (ChIP) identified FGFR3 and eIF4E as two key genes regulated by PRMT5. PRMT5 knockdown reduced the levels of H4R3me2s and H3R8me2s methylation on FGFR3 and eIF4E promoters, leading to decreased expressions of FGFR3 and eIF4E. Collectively, our findings provide new evidence that PRMT5 plays an important role in CRC pathogenesis through epigenetically regulating arginine methylation of oncogenes such as eIF4E and FGFR3.

Citing Articles

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