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. Grandis; Scott Kopetz; Mien Chie Hung

doi:10.1172/JCI82826

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

Biological, Environmental Sciences and Engineering

Research output: Contribution to journal › Article › peer-review

114 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 language	English (US)
Pages (from-to)	4529-4543
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	125
Issue number	12
DOIs	https://doi.org/10.1172/JCI82826
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1172/JCI82826

Cite this

Liao, H. W., Hsu, J. M., Xia, W., Wang, H. L., Wang, Y. N., Chang, W. C., Arold, S. T., Chou, C. K., Tsou, P. H., Yamaguchi, H., Fang, Y. F., Lee, H. J., Lee, H. H., Tai, S. K., Yang, M. H., Morelli, M. P., Sen, M., Ladbury, J. E., Chen, C. H., ... Hung, M. C. (2015). PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. Journal of Clinical Investigation, 125(12), 4529-4543. https://doi.org/10.1172/JCI82826

@article{ca585b60db9f4b9ab7fed49a0b051396,

title = "PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response",

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.",

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

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.",

year = "2015",

month = dec,

doi = "10.1172/JCI82826",

language = "English (US)",

volume = "125",

pages = "4529--4543",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

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Liao, HW, Hsu, JM, Xia, W, Wang, HL, Wang, YN, Chang, WC, Arold, ST, Chou, CK, Tsou, PH, Yamaguchi, H, Fang, YF, Lee, HJ, Lee, HH, Tai, SK, Yang, MH, Morelli, MP, Sen, M, Ladbury, JE, Chen, CH, Grandis, JR, Kopetz, S & Hung, MC 2015, 'PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response', Journal of Clinical Investigation, vol. 125, no. 12, pp. 4529-4543. https://doi.org/10.1172/JCI82826

TY - JOUR

T1 - PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

AU - Liao, Hsin Wei

AU - Hsu, Jung Mao

AU - Xia, Weiya

AU - Wang, Hung Ling

AU - Wang, Ying Nai

AU - Chang, Wei Chao

AU - Arold, Stefan T.

AU - Chou, Chao Kai

AU - Tsou, Pei Hsiang

AU - Yamaguchi, Hirohito

AU - Fang, Yueh Fu

AU - Lee, Hong Jen

AU - Lee, Heng Huan

AU - Tai, Shyh Kuan

AU - Yang, Mhu Hwa

AU - Morelli, Maria P.

AU - Sen, Malabika

AU - Ladbury, John E.

AU - Chen, Chung Hsuan

AU - Grandis, Jennifer R.

AU - Kopetz, Scott

AU - Hung, Mien Chie

N1 - 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.

PY - 2015/12

Y1 - 2015/12

N2 - 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.

AB - 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.

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U2 - 10.1172/JCI82826

DO - 10.1172/JCI82826

M3 - Article

C2 - 26571401

AN - SCOPUS:84948798342

SN - 0021-9738

VL - 125

SP - 4529

EP - 4543

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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