Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation

• Published in: PloS one Vol. 13; no. 6; p. e0197372
• Main Authors: Thomenius, Michael J, Totman, Jennifer, Harvey, Darren, Mitchell, Lorna H, Riera, Thomas V, Cosmopoulos, Kat, Grassian, Alexandra R, Klaus, Christine, Foley, Megan, Admirand, Elizabeth A, Jahic, Haris, Majer, Christina, Wigle, Tim, Jacques, Suzanne L, Gureasko, Jodi, Brach, Dorothy, Lingaraj, Trupti, West, Kip, Smith, Sherri, Rioux, Nathalie, Waters, Nigel J, Tang, Cuyue, Raimondi, Alejandra, Munchhof, Michael, Mills, James E, Ribich, Scott, Porter Scott, Margaret, Kuntz, Kevin W, Janzen, William P, Moyer, Mikel, Smith, Jesse J, Chesworth, Richard, Copeland, Robert A, Boriack-Sjodin, P Ann
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-06-2018; Public Library of Science (PLoS)
• Subjects: 60 APPLIED LIFE SCIENCES; A549 Cells; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; Biology and Life Sciences; Cancer; Cancer cells; Cancer research; Cancer treatment; Carcinogenesis; Carcinogenesis - drug effects; Carcinogenesis - genetics; Cell proliferation; Cell Proliferation - drug effects; Clinical trials; CRISPR; CRISPR-Cas Systems; Engineering and Technology; Enzymatic activity; Enzyme inhibitors; Enzyme Inhibitors - pharmacology; Enzymes; Esophagus; Genetic aspects; Health aspects; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - chemistry; Histone-Lysine N-Methyltransferase - genetics; Humans; Inhibitors; Kinases; Lysine; Macromolecules; Medicine and Health Sciences; Methylation; Methylation - drug effects; Methyltransferases; Methyltransferases - antagonists & inhibitors; Molecular chains; Mutagenesis; Organic chemistry; Pharmacology; Phenotypes; Physical Sciences; Physiological aspects; Precision medicine; Proteins; Proteomics; RNA Interference; RNA-mediated interference; Small Molecule Libraries - pharmacology; Small molecules; Tumor necrosis factor-TNF; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0197372

A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules. To address this issue, a variety of genetic, molecular and chemical tools can be used. All of these approaches can produce misleading results if the specificity of the tools is not well understood and the proper controls are not performed. In this paper we illustrate these general themes by providing detailed studies of small molecule inhibitors of the enzymatic activity of two members of the SMYD branch of the protein lysine methyltransferases, SMYD2 and SMYD3. We show that tool compounds as well as CRISPR/Cas9 fail to reproduce many of the cell proliferation findings associated with SMYD2 and SMYD3 inhibition previously obtained with RNAi based approaches and with early stage chemical probes.