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Elife. 2019 Oct 28;8. pii: e47110. doi: 10.7554/eLife.47110. [Epub ahead of print]

A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.

Author information

1
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
2
Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, United States.
3
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States.
4
Structural Genomics Consortium, University of Toronto, Toronto, Canada.
5
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States.
6
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
7
Center for Synthetic and Systematic Biology, Tsinghua University, Beijing, China.
8
Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China.
9
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States.

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.

KEYWORDS:

biochemistry; chemical biology; human

PMID:
31657716
DOI:
10.7554/eLife.47110
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