2. Academic Validation
  3. Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

  • Cell Death Dis. 2018 Feb 27;9(3):326. doi: 10.1038/s41419-018-0347-x.
Linda Xiaoyan Li 1,  Julie Xia Zhou 1,  James P Calvet 2 3,  Andrew K Godwin 4,  Roy A Jensen 4,  Xiaogang Li 5 6 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 2 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 3 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 4 Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 5 Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA. xli3@kumc.edu.
  • 6 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA. xli3@kumc.edu.
  • 7 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA. xli3@kumc.edu.
PMID: 29487338 DOI: 10.1038/s41419-018-0347-x
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.

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