A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion
- Memorial Sloan Kettering Cancer Center, United States
- Weill Cornell Medical College of Cornell University, United States
- University of Wisconsin-Madison, United States
- University of Toronto, Canada
- Tsinghua University, China
- Chaoyang Hospital, Affiliation Hospital of Capital Medical University, China
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.
Data availability
The crystallographic coordinates and structural factors are deposited into the Protein Data Bank with the accession numbers of 4IKP for the CARM1-1 complex and 6D2L for CARM1-5a complex.
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Crystal structure of human CARM1 with (S)-SKI-72Protein Data Bank, 6D2L.
Article and author information
Author details
Funding
National Institutes of Health (R01GM096056)
- Minkui Luo
Susan G Komen Foundation (PDF17481306)
- Eui-jun Kim
Special Funding of Beijing Municipal Administration of Hospitals Clinical Medicine Development YangFan Project (ZYLX201713)
- Zhenyu Zhang
The Structural Genomics Consortium
- Peter J Brown
National Institutes of Health (R35GM131858)
- Minkui Luo
National Institutes of Health (R01GM120570)
- Minkui Luo
National Cancer Institute (5P30 CA008748)
- Minkui Luo
National Cancer Institute (R01CA236356)
- Wei Xu
National Cancer Institute (R01CA213293)
- Wei Xu
Starr Cancer Consortium (I8-A8-058)
- Minkui Luo
MSKCC Functional Genomics Initiative
- Minkui Luo
Mr William H Goodwin and Mrs Alice Goodwin Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center
- Minkui Luo
MSKCC Metastasis and Tumor Ecosystems Center
- Minkui Luo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Cai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion
eLife 8:e47110.
https://doi.org/10.7554/eLife.47110
Further reading
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Teichoic acids (TA) are linear phospho-saccharidic polymers and important constituents of the cell envelope of Gram-positive bacteria, either bound to the peptidoglycan as wall teichoic acids (WTA) or to the membrane as lipoteichoic acids (LTA). The composition of TA varies greatly but the presence of both WTA and LTA is highly conserved, hinting at an underlying fundamental function that is distinct from their specific roles in diverse organisms. We report the observation of a periplasmic space in Streptococcus pneumoniae by cryo-electron microscopy of vitreous sections. The thickness and appearance of this region change upon deletion of genes involved in the attachment of TA, supporting their role in the maintenance of a periplasmic space in Gram-positive bacteria as a possible universal function. Consequences of these mutations were further examined by super-resolved microscopy, following metabolic labeling and fluorophore coupling by click chemistry. This novel labeling method also enabled in-gel analysis of cell fractions. With this approach, we were able to titrate the actual amount of TA per cell and to determine the ratio of WTA to LTA. In addition, we followed the change of TA length during growth phases, and discovered that a mutant devoid of LTA accumulates the membrane-bound polymerized TA precursor.
