SMYD3 promotes the epithelial-mesenchymal transition in breast cancer.
Animals
Breast Neoplasms
/ genetics
Cell Line, Tumor
Cell Movement
/ genetics
Chromatin
/ drug effects
Epithelial-Mesenchymal Transition
/ drug effects
Female
Gene Knockdown Techniques
Histone-Lysine N-Methyltransferase
/ antagonists & inhibitors
Humans
Neoplasm Invasiveness
/ genetics
Phosphorylation
Signal Transduction
/ drug effects
Smad3 Protein
/ genetics
Transforming Growth Factor beta
/ genetics
Xenograft Model Antitumor Assays
Zebrafish
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
20 02 2019
20 02 2019
Historique:
accepted:
23
11
2018
revised:
19
11
2018
received:
19
11
2017
pubmed:
14
12
2018
medline:
21
8
2019
entrez:
14
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30544196
pii: 5245441
doi: 10.1093/nar/gky1221
pmc: PMC6379668
doi:
Substances chimiques
Chromatin
0
SMAD3 protein, human
0
Smad3 Protein
0
Transforming Growth Factor beta
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
SMYD3 protein, human
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1278-1293Informations de copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
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