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

  1. Xiao-Chuan Cai
  2. Tuo Zhang
  3. Eui-jun Kim
  4. Ming Jiang
  5. Ke Wang
  6. Junyi Wang
  7. Shi Chen
  8. Nawei Zhang
  9. Hong Wu
  10. Fengling Li
  11. Carlo C dela Seña
  12. Hong Zeng
  13. Victor Vivcharuk
  14. Xiang Niu
  15. Weihong Zheng
  16. Jonghan P Lee
  17. Yuling Chen
  18. Dalia Barsyte
  19. Magda Szewczyk
  20. Taraneh Hajian
  21. Glorymar Ibáñez
  22. Aiping Dong
  23. Ludmila Dombrovski
  24. Zhenyu Zhang
  25. Haiteng Deng
  26. Jinrong Min
  27. Cheryl H Arrowsmith
  28. Linas Mazutis
  29. Lei Shi
  30. Masoud Vedadi
  31. Peter J Brown
  32. Jenny Xiang
  33. Li-Xuan Qin
  34. Wei Xu
  35. Minkui Luo  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. Weill Cornell Medical College of Cornell University, United States
  3. University of Wisconsin-Madison, United States
  4. University of Toronto, Canada
  5. Tsinghua University, China
  6. 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.

The following data sets were generated

Article and author information

Author details

  1. Xiao-Chuan Cai

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Tuo Zhang

    Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Eui-jun Kim

    McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ming Jiang

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ke Wang

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Junyi Wang

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Shi Chen

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5860-2616
  8. Nawei Zhang

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Hong Wu

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Fengling Li

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Carlo C dela Seña

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Hong Zeng

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Victor Vivcharuk

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Xiang Niu

    Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Weihong Zheng

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Jonghan P Lee

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Yuling Chen

    Center for Synthetic and Systematic Biology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Dalia Barsyte

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  19. Magda Szewczyk

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  20. Taraneh Hajian

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  21. Glorymar Ibáñez

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Aiping Dong

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  23. Ludmila Dombrovski

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  24. Zhenyu Zhang

    Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  25. Haiteng Deng

    Center for Synthetic and Systematic Biology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  26. Jinrong Min

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  27. Cheryl H Arrowsmith

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  28. Linas Mazutis

    Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Lei Shi

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  30. Masoud Vedadi

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  31. Peter J Brown

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8454-0367
  32. Jenny Xiang

    Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  33. Li-Xuan Qin

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  34. Wei Xu

    McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  35. Minkui Luo

    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    luom@mskcc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7409-7034

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.

Reviewing Editor

  1. Wilfred A van der Donk, University of Illinois at Urbana-Champaign, United States

Version history

  1. Received: March 24, 2019
  2. Accepted: October 27, 2019
  3. Accepted Manuscript published: October 28, 2019 (version 1)
  4. Version of Record published: December 17, 2019 (version 2)
  5. Version of Record updated: October 15, 2020 (version 3)

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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  1. Xiao-Chuan Cai
  2. Tuo Zhang
  3. Eui-jun Kim
  4. Ming Jiang
  5. Ke Wang
  6. Junyi Wang
  7. Shi Chen
  8. Nawei Zhang
  9. Hong Wu
  10. Fengling Li
  11. Carlo C dela Seña
  12. Hong Zeng
  13. Victor Vivcharuk
  14. Xiang Niu
  15. Weihong Zheng
  16. Jonghan P Lee
  17. Yuling Chen
  18. Dalia Barsyte
  19. Magda Szewczyk
  20. Taraneh Hajian
  21. Glorymar Ibáñez
  22. Aiping Dong
  23. Ludmila Dombrovski
  24. Zhenyu Zhang
  25. Haiteng Deng
  26. Jinrong Min
  27. Cheryl H Arrowsmith
  28. Linas Mazutis
  29. Lei Shi
  30. Masoud Vedadi
  31. Peter J Brown
  32. Jenny Xiang
  33. Li-Xuan Qin
  34. Wei Xu
  35. Minkui Luo
(2019)
A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion
eLife 8:e47110.
https://doi.org/10.7554/eLife.47110

Share this article

https://doi.org/10.7554/eLife.47110

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