| Literature DB >> 31657716 |
Xiao-Chuan Cai1, Tuo Zhang2, Eui-Jun Kim3, Ming Jiang1,4, Ke Wang1, Junyi Wang1, Shi Chen1,5, Nawei Zhang1,6, Hong Wu7, Fengling Li7, Carlo C Dela Seña7, Hong Zeng7, Victor Vivcharuk8, Xiang Niu9,10, Weihong Zheng1, Jonghan P Lee1,5, Yuling Chen11, Dalia Barsyte7, Magda Szewczyk7, Taraneh Hajian7, Glorymar Ibáñez1, Aiping Dong7, Ludmila Dombrovski7, Zhenyu Zhang6, Haiteng Deng7,11, Jinrong Min7,12, Cheryl H Arrowsmith7,13, Linas Mazutis9, Lei Shi8, Masoud Vedadi7,14, Peter J Brown7, Jenny Xiang2, Li-Xuan Qin15, Wei Xu3, Minkui Luo1,4.
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.Entities:
Keywords: PRMT; biochemistry; chemical biology; epigenetic; human; inhibitor; mechanism; methylation; single cell
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Year: 2019 PMID： 31657716 PMCID： PMC6917500 DOI： 10.7554/eLife.47110
Source DB: PubMed Journal: Elife ISSN： 2050-084X Impact factor: 8.140