2. Academic Validation
  3. A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion

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

  • Elife. 2019 Oct 28:8:e47110. doi: 10.7554/eLife.47110.
Xiao-Chuan Cai 1,  Tuo Zhang 2,  Eui-Jun Kim 3,  Ming Jiang 1 4,  Ke Wang 1,  Junyi Wang 1,  Shi Chen 1 5,  Nawei Zhang 1 6,  Hong Wu 7,  Fengling Li 7,  Carlo C Dela Seña 7,  Hong Zeng 7,  Victor Vivcharuk 8,  Xiang Niu 9 10,  Weihong Zheng 1,  Jonghan P Lee 1 5,  Yuling Chen 11,  Dalia Barsyte 7,  Magda Szewczyk 7,  Taraneh Hajian 7,  Glorymar Ibáñez 1,  Aiping Dong 7,  Ludmila Dombrovski 7,  Zhenyu Zhang 6,  Haiteng Deng 7 11,  Jinrong Min 7 12,  Cheryl H Arrowsmith 7 13,  Linas Mazutis 9,  Lei Shi 8,  Masoud Vedadi 7 14,  Peter J Brown 7,  Jenny Xiang 2,  Li-Xuan Qin 15,  Wei Xu 3,  Minkui Luo 1 4
Affiliations

Affiliations

  • 1 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • 2 Genomics Resources Core Facility, Weill Cornell Medical College, Cornell University, New York, United States.
  • 3 McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States.
  • 4 Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, United States.
  • 5 Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States.
  • 6 Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China.
  • 7 Structural Genomics Consortium, University of Toronto, Toronto, Canada.
  • 8 Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States.
  • 9 Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • 10 Tri-Institutional PhD Program in Computational Biology and Medicine, Memorial Sloan Kettering Cancer Center, New York, United States.
  • 11 Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, China.
  • 12 Department of Physiology, University of Toronto, Toronto, Canada.
  • 13 Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, Canada.
  • 14 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
  • 15 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States.
PMID: 31657716 DOI: 10.7554/eLife.47110
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 by altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 (6a) and CARM1 knockout alter the epigenetic plasticity with remarkable difference, suggesting distinct modes of action for small-molecule and genetic perturbations. We therefore discovered a CARM1-addiction mechanism of Cancer metastasis and developed a chemical probe to target this process.

Keywords

PRMT; biochemistry; chemical biology; epigenetic; human; inhibitor; mechanism; methylation; single cell.

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