A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion Journal Article
| Authors: | Cai, X. C.; Zhang, T.; Kim, E. J.; Jiang, M.; Wang, K.; Wang, J.; Chen, S.; Zhang, N.; Wu, H.; Li, F.; Dela Seña, C. C.; Zeng, H.; Vivcharuk, V.; Niu, X.; Zheng, W.; Lee, J. P.; Chen, Y.; Barsyte, D.; Szewczyk, M.; Hajian, T.; Ibáñez, G.; Dong, A.; Dombrovsky, L.; Zhang, Z.; Deng, H.; Min, J.; Arrowsmith, C. H.; Mazutis, L.; Shi, L.; Vedadi, M.; Brown, P. J.; Xiang, J.; Qin, L. X.; Xu, W.; Luo, M. |
| Article Title: | A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion |
| Abstract: | CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 (6a in this work) is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 (6a) can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for several days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 (6a) recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73(6a)-associated reduction of invasiveness acts via altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 (6a) and CARM1 knockout alter the epigenetic plasticity with remarkable difference, arguing distinct modes of action between the small-molecule and genetic perturbation. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process. © 2019, eLife Sciences Publications Ltd. All rights reserved. |
| Keywords: | controlled study; cell proliferation; cell cycle; breast cancer; gene expression; molecular dynamics; enzyme activity; dna methylation; methyltransferase; epigenetics; hydrogen bond; crystallization; molecular docking; surface plasmon resonance; cell invasion; ligand binding; nuclear magnetic resonance; thermostability; membrane permeability; proton nuclear magnetic resonance; polyacrylamide gel electrophoresis; chemical bond; prodrug; rna sequence; carbon nuclear magnetic resonance; protein arginine methyltransferase; dna purification; ultraviolet spectroscopy; electrospray; hydrophobicity; tumor invasion; liquid chromatography-mass spectrometry; size exclusion chromatography; entropy; human; article; ic50; metabolic stability; ec50; mcf-7 cell line; cell proliferation assay; mda-mb-231 cell line; cell invasion assay |
| Journal Title: | eLife |
| Volume: | 8 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2019-01-01 |
| Start Page: | e47110 |
| Language: | English |
| DOI: | 10.7554/eLife.47110 |
| PUBMED: | 31657716 |
| PROVIDER: | scopus |
| PMCID: | PMC6917500 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2020 -- Source: Scopus |
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