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
Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here, we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although the N-terminal region of DTX3L contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3’-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3’ overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications.
