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

Handle URI:
http://hdl.handle.net/10754/599404
Title:
PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response
Authors:
Liao, Hsin-Wei; Hsu, Jung-Mao; Xia, Weiya; Wang, Hung-Ling; Wang, Ying-Nai; Chang, Wei-Chao; Arold, Stefan T. ( 0000-0001-5278-0668 ) ; Chou, Chao-Kai; Tsou, Pei-Hsiang; Yamaguchi, Hirohito; Fang, Yueh-Fu; Lee, Hong-Jen; Lee, Heng-Huan; Tai, Shyh-Kuan; Yang, Mhu-Hwa; Morelli, Maria P.; Sen, Malabika; Ladbury, John E.; Chen, Chung-Hsuan; Grandis, Jennifer R.; Kopetz, Scott; Hung, Mien-Chie
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.
Citation:
Liao H-W, Hsu J-M, Xia W, Wang H-L, Wang Y-N, et al. (2015) PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. Journal of Clinical Investigation 125: 4529–4543. Available: http://dx.doi.org/10.1172/JCI82826.
Publisher:
American Society for Clinical Investigation
Journal:
Journal of Clinical Investigation
Issue Date:
16-Nov-2015
DOI:
10.1172/JCI82826
PubMed ID:
26571401
PubMed Central ID:
PMC4665782
Type:
Article
ISSN:
0021-9738; 1558-8238
Sponsors:
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.
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Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorLiao, Hsin-Weien
dc.contributor.authorHsu, Jung-Maoen
dc.contributor.authorXia, Weiyaen
dc.contributor.authorWang, Hung-Lingen
dc.contributor.authorWang, Ying-Naien
dc.contributor.authorChang, Wei-Chaoen
dc.contributor.authorArold, Stefan T.en
dc.contributor.authorChou, Chao-Kaien
dc.contributor.authorTsou, Pei-Hsiangen
dc.contributor.authorYamaguchi, Hirohitoen
dc.contributor.authorFang, Yueh-Fuen
dc.contributor.authorLee, Hong-Jenen
dc.contributor.authorLee, Heng-Huanen
dc.contributor.authorTai, Shyh-Kuanen
dc.contributor.authorYang, Mhu-Hwaen
dc.contributor.authorMorelli, Maria P.en
dc.contributor.authorSen, Malabikaen
dc.contributor.authorLadbury, John E.en
dc.contributor.authorChen, Chung-Hsuanen
dc.contributor.authorGrandis, Jennifer R.en
dc.contributor.authorKopetz, Scotten
dc.contributor.authorHung, Mien-Chieen
dc.date.accessioned2016-02-28T05:50:29Zen
dc.date.available2016-02-28T05:50:29Zen
dc.date.issued2015-11-16en
dc.identifier.citationLiao H-W, Hsu J-M, Xia W, Wang H-L, Wang Y-N, et al. (2015) PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. Journal of Clinical Investigation 125: 4529–4543. Available: http://dx.doi.org/10.1172/JCI82826.en
dc.identifier.issn0021-9738en
dc.identifier.issn1558-8238en
dc.identifier.pmid26571401en
dc.identifier.doi10.1172/JCI82826en
dc.identifier.urihttp://hdl.handle.net/10754/599404en
dc.description.abstractPosttranslational 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.en
dc.description.sponsorshipWe 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.en
dc.publisherAmerican Society for Clinical Investigationen
dc.titlePRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab responseen
dc.typeArticleen
dc.identifier.journalJournal of Clinical Investigationen
dc.identifier.pmcidPMC4665782en
dc.contributor.institutionUniversity of Texas M. D. Anderson Cancer Center, Houston, United Statesen
dc.contributor.institutionUniversity of Texas Graduate School of Biomedical Sciences at Houston, Houston, United Statesen
dc.contributor.institutionChina Medical University Taichung, Taichung, Taiwanen
dc.contributor.institutionAsia University Taiwan, Wufong, Taiwanen
dc.contributor.institutionKing Abdullah University of Science and Technology, Jeddah, Saudi Arabiaen
dc.contributor.institutionChang Gung Memorial Hospital, Taipei, Taiwanen
dc.contributor.institutionVeterans General Hospital-Taipei, Taipei, Taiwanen
dc.contributor.institutionNational Yang-Ming University Taiwan, Taipei, Taiwanen
dc.contributor.institutionUniversity of Pittsburgh Medical Center, Pittsburgh, United Statesen
dc.contributor.institutionUniversity of Leeds, Leeds, United Kingdomen
dc.contributor.institutionGenomics Research Center, Academia Sinica, Nankang, Taiwanen
dc.contributor.institutionUniversity of California, San Francisco, San Francisco, United Statesen
kaust.authorArold, Stefan T.en

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