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
N 6,2’-O-dimethyladenosine (m6Am) is a modified nucleotide located at the first transcribed position in mRNA and snRNA that is essential for diverse physiological processes. m6Am mapping methods assume each gene uses a single start nucleotide. However, gene transcription usually involves multiple start sites, generating numerous 5’ isoforms. Thus, gene-level annotations cannot capture the diversity of m6Am modification in the transcriptome. Here, we describe CROWN-seq, which simultaneously identifies transcription-start nucleotides and quantifies m6Am stoichiometry for each 5’ isoform that initiates with adenosine. Using CROWN-seq, we map the m6Am landscape in nine human cell lines. Our findings reveal that m6Am is nearly always a high stoichiometry modification, with only a small subset of cellular mRNAs showing lower m6Am stoichiometry. We find that m6Am is associated with increased transcript expression and provide evidence that m6Am may be linked to transcription initiation associated with specific promoter sequences and initiation mechanisms. These data suggest a potential new function for m6Am in influencing transcription.
