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A SMYD3 Small‐Molecule Inhibitor Impairing Cancer Cell Growth
Author(s) -
Peserico Alessia,
Germani Aldo,
Sanese Paola,
Barbosa Armenio Jorge,
Di Virgilio Valeria,
Fittipaldi Raffaella,
Fabini Edoardo,
Bertucci Carlo,
Varchi Greta,
Moyer Mary Pat,
Caretti Giuseppina,
Del Rio Alberto,
Simone Cristiano
Publication year - 2015
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24975
Subject(s) - biology , cancer research , cancer , carcinogenesis , cell growth , methyltransferase , druggability , cancer cell , epigenetics , downregulation and upregulation , small hairpin rna , rna interference , microbiology and biotechnology , gene knockdown , rna , cell culture , gene , genetics , methylation
SMYD3 is a histone lysine methyltransferase that plays an important role in transcriptional activation as a member of an RNA polymerase complex, and its oncogenic role has been described in different cancer types. We studied the expression and activity of SMYD3 in a preclinical model of colorectal cancer (CRC) and found that it is strongly upregulated throughout tumorigenesis both at the mRNA and protein level. Our results also showed that RNAi‐mediated SMYD3 ablation impairs CRC cell proliferation indicating that SMYD3 is required for proper cancer cell growth. These data, together with the importance of lysine methyltransferases as a target for drug discovery, prompted us to carry out a virtual screening to identify new SMYD3 inhibitors by testing several candidate small molecules. Here we report that one of these compounds (BCI‐121) induces a significant reduction in SMYD3 activity both in vitro and in CRC cells, as suggested by the analysis of global H3K4me2/3 and H4K5me levels. Of note, the extent of cell growth inhibition by BCI‐121 was similar to that observed upon SMYD3 genetic ablation. Most of the results described above were obtained in CRC; however, when we extended our observations to tumor cell lines of different origin, we found that SMYD3 inhibitors are also effective in other cancer types, such as lung, pancreatic, prostate, and ovarian. These results represent the proof of principle that SMYD3 is a druggable target and suggest that new compounds capable of inhibiting its activity may prove useful as novel therapeutic agents in cancer treatment. J. Cell. Physiol. 230: 2447–2460, 2015. © 2015 Wiley Periodicals, Inc.