title: WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer.
abstract: While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR. WHSC1L1-mediated methylation of EGFR in the nucleus enhanced its interaction with PCNA in squamous cell carcinoma of the head and neck (SCCHN) cells and resulted in enhanced DNA synthesis and cell cycle progression. Overall, our study demonstrates the multifaceted oncogenic function of the protein lysine methyltransferase WHSC1L1 in SCCHN, which is mediated through direct non-histone methylation of the EGFR protein with effects both in its cytoplasmic and nuclear functions.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, USA.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Saloura
authors.affiliation: Department of Medicine, University of Chicago, Chicago, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Vougiouklakis
authors.affiliation: Department of Medicine, University of Chicago, Chicago, USA.
authors.forename: Makda
authors.initials: M
authors.lastname: Zewde
authors.affiliation: Department of Medicine, University of Chicago, Chicago, USA.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Medicine, University of Chicago, Chicago, USA.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.affiliation: Department of Medicine, University of Chicago, Chicago, USA.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: OncoTherapy Science Inc., Kawasaki, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Pathology, University of Chicago, Chicago, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lingen
authors.affiliation: Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Dohmae
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, USA.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, USA.|Department of Surgery, University of Chicago, Chicago, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004261:DNA Replication; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D011495:Histone-Lysine N-Methyltransferase; C432968:NSD3 protein, human; D066246:ErbB Receptors; D008239:Lysine