• 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 (2019-10-29)
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

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.

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