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
- Structural Biology and Molecular Biophysics
Inhibition of Bruton’s tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders, and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib, and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph et al., 2020). Here, we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.
