eLife (Oct 2019)
A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion
- Xiao-Chuan Cai,
- Tuo Zhang,
- Eui-jun Kim,
- Ming Jiang,
- Ke Wang,
- Junyi Wang,
- Shi Chen,
- Nawei Zhang,
- Hong Wu,
- Fengling Li,
- Carlo C dela Seña,
- Hong Zeng,
- Victor Vivcharuk,
- Xiang Niu,
- Weihong Zheng,
- Jonghan P Lee,
- Yuling Chen,
- Dalia Barsyte,
- Magda Szewczyk,
- Taraneh Hajian,
- Glorymar Ibáñez,
- Aiping Dong,
- Ludmila Dombrovski,
- Zhenyu Zhang,
- Haiteng Deng,
- Jinrong Min,
- Cheryl H Arrowsmith,
- Linas Mazutis,
- Lei Shi,
- Masoud Vedadi,
- Peter J Brown,
- Jenny Xiang,
- Li-Xuan Qin,
- Wei Xu,
- Minkui Luo
Affiliations
- Xiao-Chuan Cai
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Tuo Zhang
- Genomics Resources Core Facility, Weill Cornell Medical College, Cornell University, New York, United States
- Eui-jun Kim
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
- Ming Jiang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, United States
- Ke Wang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Junyi Wang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Shi Chen
- ORCiD
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States
- Nawei Zhang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China
- Hong Wu
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Fengling Li
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Carlo C dela Seña
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Hong Zeng
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Victor Vivcharuk
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
- Xiang Niu
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Tri-Institutional PhD Program in Computational Biology and Medicine, Memorial Sloan Kettering Cancer Center, New York, United States
- Weihong Zheng
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Jonghan P Lee
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States
- Yuling Chen
- Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, China
- Dalia Barsyte
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Magda Szewczyk
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Taraneh Hajian
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Glorymar Ibáñez
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Aiping Dong
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Ludmila Dombrovski
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Zhenyu Zhang
- Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China
- Haiteng Deng
- Structural Genomics Consortium, University of Toronto, Toronto, Canada; Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, China
- Jinrong Min
- Structural Genomics Consortium, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada
- Cheryl H Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, Canada; Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, Canada
- Linas Mazutis
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Lei Shi
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
- Masoud Vedadi
- Structural Genomics Consortium, University of Toronto, Toronto, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
- Peter J Brown
- ORCiD
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
- Jenny Xiang
- Genomics Resources Core Facility, Weill Cornell Medical College, Cornell University, New York, United States
- Li-Xuan Qin
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
- Wei Xu
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
- Minkui Luo
- ORCiD
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, United States
- DOI
- https://doi.org/10.7554/eLife.47110
- Journal volume & issue
-
Vol. 8
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
