A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion PMID: 31657716

Target-related Cytokines

2026-09-23

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

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.

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.