TY - JOUR T1 - A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion JF - bioRxiv DO - 10.1101/591164 SP - 591164 AU - Xiao-Chuan Cai AU - Tuo Zhang AU - Eui-jun Kim AU - Ming Jiang AU - Ke Wang AU - Junyi Wang AU - Shi Chen AU - Nawei Zhang AU - Hong Wu AU - Fengling Li AU - Carlo C. dela Seña AU - Hong Zheng AU - Victor Vivcharuk AU - Xiang Niu AU - Weihong Zheng AU - Jonghan P. Lee AU - Yuling Chen AU - Dalia Barsyte AU - Magda Szewczyk AU - Taraneh Hajian AU - Glorymar Ibáñez AU - Aiping Dong AU - Ludmila Dombrovsky AU - Zhenyu Zhang AU - Haiteng Deng AU - Jinrong Min AU - Cheryl H. Arrowsmith AU - Linas Mazutis AU - Lei Shi AU - Masoud Vedadi AU - Peter J. Brown AU - Jenny Xiang AU - Li-Xuan Qin AU - Wei Xu AU - Minkui Luo Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/03/27/591164.abstract N2 - 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. ER -