PUBLICATION

SMYD3 promotes the epithelial-mesenchymal transition in breast cancer

Authors
Fenizia, C., Bottino, C., Corbetta, S., Fittipaldi, R., Floris, P., Gaudenzi, G., Carra, S., Cotelli, F., Vitale, G., Caretti, G.
ID
ZDB-PUB-181215-12
Date
2018
Source
Nucleic acids research   47(3): 1278-1293 (Journal)
Registered Authors
Cotelli, Franco
Keywords
none
MeSH Terms
  • Animals
  • Breast Neoplasms/genetics*
  • Breast Neoplasms/pathology
  • Cell Line, Tumor
  • Cell Movement/genetics
  • Chromatin/drug effects
  • Epithelial-Mesenchymal Transition/drug effects
  • Female
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase/antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase/genetics*
  • Humans
  • Neoplasm Invasiveness/genetics
  • Neoplasm Invasiveness/pathology
  • Phosphorylation
  • Signal Transduction/drug effects
  • Smad3 Protein/genetics*
  • Transforming Growth Factor beta/genetics*
  • Xenograft Model Antitumor Assays
  • Zebrafish
PubMed
30544196 Full text @ Nucleic Acids Res.
Abstract
SMYD3 is a methylase previously linked to cancer cell invasion and migration. Here we show that SMYD3 favors TGFβ-induced epithelial-mesenchymal transition (EMT) in mammary epithelial cells, promoting mesenchymal and EMT transcription factors expression. SMYD3 directly interacts with SMAD3 but it is unnecessary for SMAD2/3 phosphorylation and nuclear translocation. Conversely, SMYD3 is indispensable for SMAD3 direct association to EMT genes regulatory regions. Accordingly, SMYD3 knockdown or its pharmacological blockade with the BCI121 inhibitor dramatically reduce TGFβ-induced SMAD3 association to the chromatin. Remarkably, BCI121 treatment attenuates mesenchymal genes transcription in the mesenchymal-like MDA-MB-231 cell line and reduces their invasive ability in vivo, in a zebrafish xenograft model. In addition, clinical datasets analysis revealed that higher SMYD3 levels are linked to a less favorable prognosis in claudin-low breast cancers and to a reduced metastasis free survival in breast cancer patients. Overall, our data point at SMYD3 as a pivotal SMAD3 cofactor that promotes TGFβ-dependent mesenchymal gene expression and cell migration in breast cancer, and support SMYD3 as a promising pharmacological target for anti-cancer therapy.
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