Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

Linda Xiaoyan Li, Julie Xia Zhou, James P. Calvet, Andrew K. Godwin, Roy A. Jensen, Xiaogang Li

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

We identified SMYD2, a SMYD (SET and MYND domain) family protein with lysine methyltransferase activity, as a novel breast cancer oncogene. SMYD2 was expressed at significantly higher levels in breast cancer cell lines and in breast tumor tissues. Silencing of SMYD2 by RNAi in triple-negative breast cancer (TNBC) cell lines or inhibition of SMYD2 with its specific inhibitor, AZ505, significantly reduced tumor growth in vivo. SMYD2 executes this activity via methylation and activation of its novel non-histone substrates, including STAT3 and the p65 subunit of NF-κB, leading to increased TNBC cell proliferation and survival. There are cross-talk and synergistic effects among SMYD2, STAT3, and NF-κB in TNBC cells, in that STAT3 can contribute to the modification of NF-κB p65 subunit post-translationally by recruitment of SMYD2, whereas the p65 subunit of NF-κB can also contribute to the modification of STAT3 post-translationally by recruitment of SMYD2, leading to methylation and activation of STAT3 and p65 in these cells. The expression of SMYD2 can be upregulated by IL-6-STAT3 and TNFα-NF-κB signaling, which integrates epigenetic regulation to inflammation in TNBC development. In addition, we have identified a novel SMYD2 transcriptional target gene, PTPN13, which links SMYD2 to other known breast cancer associated signaling pathways, including ERK, mTOR, and Akt signaling via PTPN13 mediated phosphorylation.

Original languageEnglish (US)
Article number326
JournalCell Death and Disease
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Methyltransferases
Lysine
Breast Neoplasms
Methylation
Histone-Lysine N-Methyltransferase
Cell Line
MAP Kinase Signaling System
RNA Interference
Oncogenes
Epigenomics
Interleukin-6
Cell Survival
Phosphorylation
Cell Proliferation
Inflammation
Growth
Genes
Neoplasms

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression. / Li, Linda Xiaoyan; Zhou, Julie Xia; Calvet, James P.; Godwin, Andrew K.; Jensen, Roy A.; Li, Xiaogang.

In: Cell Death and Disease, Vol. 9, No. 3, 326, 01.03.2018.

Research output: Contribution to journalArticle

Li, Linda Xiaoyan ; Zhou, Julie Xia ; Calvet, James P. ; Godwin, Andrew K. ; Jensen, Roy A. ; Li, Xiaogang. / Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression. In: Cell Death and Disease. 2018 ; Vol. 9, No. 3.
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