title: Targeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3.
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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.|Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Baolai
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Ruiming
authors.initials: R
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Bu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009282:Naphthalenesulfonates / Q000494:pharmacology*; D029543:Nucleocytoplasmic Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C535077:7,7'-carbonylbis(azanediyl) bis(4-hydroxynaphthalene-2-sulfonic acid; C411571:EIF4ENIF1 protein, human; D009282:Naphthalenesulfonates; D029543:Nucleocytoplasmic Transport Proteins; D034741:RNA, Small Interfering; D014508:Urea; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: AMI-1; FGFR3; PRMT5; colorectal cancer; eIF4E