A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion

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Xiao-Chuan Cai

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Biochemistry

Tuo Zhang

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Biochemistry

Eui-jun Kim

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Biochemistry

Ming Jiang

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Biochemistry

Ke Wang

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Biochemistry

Junyi Wang

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Biochemistry

Shi Chen

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Biochemistry

Nawei Zhang

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Biochemistry

Hong Wu

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Biochemistry

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Fengling Li

Carlo C. dela Seña

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Biochemistry

Hong Zheng

Victor Vivcharuk

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Biochemistry

Xiang Niu

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Biochemistry

Weihong Zheng

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Biochemistry

Jonghan P. Lee

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Biochemistry

Yuling Chen

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Biochemistry

Dalia Barsyte

Magda Szewczyk

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Biochemistry

Taraneh Hajian

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Biochemistry

Glorymar Ibáñez

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Biochemistry

Aiping Dong

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Biochemistry Cell Biology

Ludmila Dombrovsky

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Biochemistry

Zhenyu Zhang

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Biochemistry

Haiteng Deng

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Biochemistry

Jinrong Min

Cheryl H Arrowsmith

Linas Mazutis

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Biochemistry

Lei Shi

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Biochemistry

Masoud Vedadi

Peter J Brown

Jenny Xiang

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Biochemistry

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Published in eLife, 2019-10-28

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 is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73-associated reduction of invasiveness act via altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 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.

Biochemistry
Biochemistry 9 Projects