PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

Hsin Wei Liao, Jung Mao Hsu, Weiya Xia, Hung Ling Wang, Ying Nai Wang, Wei Chao Chang, Stefan T. Arold, Chao Kai Chou, Pei Hsiang Tsou, Hirohito Yamaguchi, Yueh Fu Fang, Hong Jen Lee, Heng Huan Lee, Shyh Kuan Tai, Mhu Hwa Yang, Maria P. Morelli, Malabika Sen, John E. Ladbury, Chung Hsuan Chen, Jennifer R. GrandisScott Kopetz, Mien Chie Hung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.

Original languageEnglish (US)
Pages (from-to)4529-4543
Number of pages15
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
StatePublished - Dec 2015

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: We thank Jennifer L. Hsu for critical reading of the manuscript; Su Zhang, Jian-Guang Shi, Zhen-Bo Han, and Jin-Fong Lee for technical assistance; Zhen Fan for providing GEO and HT29 colorectal cancer cell line; Xiangbo Wan for providing patient samples; The National Cancer Institute for providing colorectal tissue microarrays; The Cancer Center Support Grant–funded (CA016672) Characterized Cell Line Core for performing STR DNA fingerprinting; and ShRNA/ORFeome Core Facility for providing shRNA constructs. Funding was provided by NIH (CA109311, CA099031, and CCSG CA16672 to M.C. Hung; P50CA097190 to J.R. Grandis); Cancer Prevention and Research Institute of Texas (RP150245); The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (to M.C. Hung); Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE; MOST 104-2911-I-002-302); Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TDU-B-212-124-002); Center for Biological Pathways; and the American Cancer Society (to J.R. Grandis). Research by S.T. Arold reported in this publication was supported by KAUST.
This publication acknowledges KAUST support, but has no KAUST affiliated authors.

ASJC Scopus subject areas

  • General Medicine

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