SMYD3 promotes the epithelial-mesenchymal transition in breast cancer

Claudio Fenizia, Cinzia Bottino, Silvia Corbetta, Raffaella Fittipaldi, Pamela Floris, Germano Gaudenzi, Silvia Carra, Franco Cotelli, Giovanni Vitale, Giuseppina Caretti

Research output: Contribution to journalArticle

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 MDAMB- 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.

Original languageEnglish
Pages (from-to)1278-1293
Number of pages16
JournalNucleic Acids Research
Volume47
Issue number3
DOIs
Publication statusPublished - Jan 1 2019

ASJC Scopus subject areas

  • Genetics

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    Fenizia, C., Bottino, C., Corbetta, S., Fittipaldi, R., Floris, P., Gaudenzi, G., Carra, S., Cotelli, F., Vitale, G., & Caretti, G. (2019). SMYD3 promotes the epithelial-mesenchymal transition in breast cancer. Nucleic Acids Research, 47(3), 1278-1293. https://doi.org/10.1093/nar/gky1221