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

• DOI: 10.1371/journal.pone.0197372
• Publication Date: 2018-06-01T17:40:26Z
• Authors: Michael J. Thomenius; Jennifer Totman; Darren Harvey; Lorna H. Mitchell; Thomas V. Riera; Kat Cosmopoulos; Alexandra R. Gras...; Christine Klaus; Megan Foley; Elizabeth A. Admi...; Haris Jahic; Christina Majer; Tim Wigle; Suzanne L. Jacques; Jodi Gureasko; Dorothy Brach; Trupti Lingaraj; Kip West; Sherri Smith; Nathalie Rioux; Nigel J. Waters; Cuyue Tang; Alejandra Raimondi; Michael Munchhof; James E. Mills; Scott Ribich; Margaret Porter S...; Kevin W. Kuntz; William P. Janzen; Mikel Moyer; Jesse J. Smith; Richard Chesworth; Robert A. Copeland; P. Ann Boriack-Sj...
• Keywords: 0301 basic medicine; Carcinogenesis; Science; Q; R; Adenocarcinoma of Lung; Histone-Lysine N-Methyltransferase; Methyltransferases; Methylation; 3. Good health; Small Molecule Libraries; 03 medical and health sciences; A549 Cells; Medicine; Humans; RNA Interference; CRISPR-Cas Systems; Enzyme Inhibitors; Research Article; Cell Proliferation

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