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Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization

Yuichiro Yoshioka1,2, Takehiro Suzuki3, Yo Matsuo4

  • 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave, MC2115, Chicago, Illinois, 60637.

Cancer Medicine
|June 23, 2017
PubMed

Insights

Protein lysine methyltransferase SMYD3 methylates HER2 at lysine 175, enhancing HER2 homodimerization and autophosphorylation. This SMYD3-mediated methylation pathway presents a potential target for novel anti-cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • HER2 (Human Epidermal growth factor Receptor 2) is a receptor tyrosine kinase overexpressed in various cancers, including breast and gastric cancers.
  • HER2 amplification and overexpression are linked to cancer progression, though its specific ligands remain unidentified.
  • HER2 homodimerization is crucial for its activation and is thought to depend on expression levels.

Purpose of the Study:

  • To investigate the role of protein lysine methyltransferase SMYD3 in HER2 homodimerization.
  • To elucidate the specific site of HER2 methylation by SMYD3 and its functional consequences.

Main Methods:

  • Investigated SMYD3-mediated methylation of HER2.
  • Utilized site-directed mutagenesis to substitute lysine 175 of HER2 with alanine (HER2-K175A).
  • Assessed HER2 homodimerization, autophosphorylation, and SMYD3's effect in breast cancer cells via knockdown experiments.

Main Results:

  • Demonstrated that SMYD3 trimethylates HER2 protein at lysine 175.
  • Showed that SMYD3 enhances HER2 homodimerization, while the HER2-K175A mutant exhibits reduced homodimer formation.
  • Found that HER2-K175A displays lower autophosphorylation levels compared to wild-type HER2, and SMYD3 knockdown attenuates this phosphorylation in cancer cells.

Conclusions:

  • SMYD3-mediated methylation of HER2 at Lysine 175 regulates HER2 homodimer formation and subsequent autophosphorylation.
  • The SMYD3-mediated methylation pathway represents a promising target for developing novel anti-cancer therapeutics.
Keywords:
HER2SMYD3human cancerlysine methylation

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