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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MSK Authors
  1. Li-Xuan Qin
    141 Qin
  2. Weihong Zheng
    11 Zheng
  3. Minkui Luo
    63 Luo
  4. Xiaochuan   Cai
    4 Cai
  5. Junyi   Wang
    5 Wang
  6. Shi Chen
    10 Chen
  7. Linas Mazutis
    23 Mazutis
  8. Ming Jiang
    2 Jiang
  9. Ke Wang
    2 Wang
  10. Nawei Zhang
    2 Zhang
  11. Jonghan Peter Lee
    3 Lee