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PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response
Hsin-Wei Liao, … , Scott Kopetz, Mien-Chie Hung
Hsin-Wei Liao, … , Scott Kopetz, Mien-Chie Hung
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4529-4543. https://doi.org/10.1172/JCI82826.
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Research Article Cell biology Oncology Article has an altmetric score of 17

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

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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.

Authors

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

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Figure 3

PRMT1 upregulates EGFR signaling and cell proliferation in colorectal cancer cell lines.

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PRMT1 upregulates EGFR signaling and cell proliferation in colorectal ca...
(A and B) Immunoblots comparing pEGFR, pERK, and pAKT levels upon EGF stimulation for indicated time in SKCO1 (A) and GEO (B) cells expressing PRMT1 or control vector. (C and D) Immunoblots evaluating pEGFR, pERK and pAKT levels upon EGF stimulation for indicated time in SKCO1 cells expressing 2 different PRMT1 shRNAs or control vector. Blots shown are representative of 3 independent experiments. (E and F) Cell proliferation assay of SKCO1 (E) and GEO (F) cells expressing PRMT1 or vector control with or without gefitinib treatment. *P < 0.05 using Student’s t-test. (G) Anchorage-independent growth of 1,000 SKCO1 exogenously expressing PRMT1 and control vector with or without gefitinib treatment. **P < 0.005 using Student’s t-test. All quantitative data were generated from 5 replicates. Data are expressed as mean ± SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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