As a result, the roles of epigenetic modulation of gene expression and protein function in breast cancer have become a major focus of scientific investigation 2, 3, 4. A major barrier to developing TNBC therapies is our lack of understanding of the molecular drivers of TNBC. The challenges of TNBC are in fact more fundamental than insensitivity to current available therapeutics.
Due to the loss of three important receptors, TNBC is more difficult to treat and more likely to recur. Triple-negative breast cancer (TNBC), in which the expression of estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 are lacking, is a common and aggressive subtype of breast cancer with poor prognostic outcome and reduced short-term survival compared with other types of breast cancer 1. 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. 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. 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. 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. 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 was expressed at significantly higher levels in breast cancer cell lines and in breast tumor tissues.
We identified SMYD2, a SMYD (SET and MYND domain) family protein with lysine methyltransferase activity, as a novel breast cancer oncogene.
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