TY - JOUR
T1 - Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression
AU - Li, Linda Xiaoyan
AU - Zhou, Julie Xia
AU - Calvet, James P.
AU - Godwin, Andrew K.
AU - Jensen, Roy A.
AU - Li, Xiaogang
N1 - Funding Information:
We acknowledge Dr. Joan Lewis-Wambi and Dr. Christy Hagan for providing us the T47D cells. We acknowledge Dr. Bruno Hagenbuch for helping us with the in vitro methylation assays. X. Li acknowledges support from National Institutes of Health grant R01 DK084097 and P30 DK106912. J.P. Calvet acknowledges support from the PKD Foundation and from the Kansas Research and Translation Core Center (P30 DK106912). A.K. Godwin and R. Jensen acknowledge support from National Institutes of Health grant P30 CA168524. L.X. Li acknowledges support from a post-doctoral fellowship funded by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (P20 GM103418). J.X. Zhou acknowledges support from the NIH K01 DK107729.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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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U2 - 10.1038/s41419-018-0347-x
DO - 10.1038/s41419-018-0347-x
M3 - Article
C2 - 29487338
AN - SCOPUS:85042687717
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 3
M1 - 326
ER -