A SMYD3 Small-Molecule Inhibitor Impairing Cancer Cell Growth.
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.
Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy.|National Cancer Institute, IRCCS Oncologico Giovanni Paolo II, Bari, Italy.
Alessia
A
Peserico
Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy.
Aldo
A
Germani
Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy.
Paola
P
Sanese
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, Bologna, Italy.
Armenio Jorge
AJ
Barbosa
Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy.
Valeria
V
Di Virgilio
Department of Biosciences, University of Milan, Milan, Italy.
Raffaella
R
Fittipaldi
Dipartimento di Farmacia e Biotecnologie, University of Bologna, Bologna, Italy.
Edoardo
E
Fabini
Dipartimento di Farmacia e Biotecnologie, University of Bologna, Bologna, Italy.
Carlo
C
Bertucci
Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna, Italy.
Greta
G
Varchi
INCELL Corporation, San Antonio, Texas.
Mary Pat
MP
Moyer
Department of Biosciences, University of Milan, Milan, Italy.
Giuseppina
G
Caretti
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, Bologna, Italy.|Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna, Italy.
Alberto
A
Del Rio
Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari "Aldo Moro", Bari, Italy.|National Cancer Institute, IRCCS Oncologico Giovanni Paolo II, Bari, Italy.
Cristiano
C
Simone
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D051379:Mice; D034622:RNA Interference / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation
D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human; C582787:Smyd3 protein, mouse