Date of Graduation
8-2015
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Mien-Chie Hung, Ph.D
Committee Member
Dihua Yu, M.D., Ph.D.
Committee Member
Hui-Kuan Lin, Ph.D.
Committee Member
Liuqing Yang, Ph.D.
Committee Member
Pierre D. McCrea, Ph.D.
Abstract
Protein modifications of epidermal growth factor receptor (EGFR) intracellular domain are well known regulators of EGFR functions whereas those of its extracellular domain remain relatively unexplored. Here, we report that methylation at R198 and R200 of EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) upregulates its binding to EGF and subsequent receptor dimerization and signaling activation. Methylation-defective EGFR mutant reduced tumor growth in mouse orthotopic xenograft model. Importantly, increased EGFR methylation sustains its signaling activation and cell proliferation in the presence of therapeutic EGFR monoclonal antibody, cetuximab. EGFR methylation level also correlates with higher recurrence rate after cetuximab treatment and poorer overall survival in colorectal cancer patients. These data suggest that R198/R200 methylation plays important role in regulating EGFR functionality and resistance to cetuximab treatment.
Keywords
PRMT1, EGFR, methylation, cetuximab, colorectal cancer