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

被引：40

作者：

Cai, Xiao-Chuan ^{[1
]}

Zhang, Tuo ^{[2
]}

Kim, Eui-jun ^{[3
]}

Jiang, Ming ^{[1
,4
]}

Wang, Ke ^{[1
]}

Wang, Junyi ^{[1
]}

Chen, Shi ^{[1
,5
]}

Zhang, Nawei ^{[1
,6
]}

Wu, Hong ^{[7
]}

Li, Fengling ^{[7
]}

dela Sena, Carlo C. ^{[7
]}

Zeng, Hong ^{[7
]}

Vivcharuk, Victor ^{[8
]}

Niu, Xiang ^{[9
,10
]}

Zheng, Weihong ^{[1
]}

Lee, Jonghan P. ^{[1
,5
]}

Chen, Yuling ^{[11
]}

Barsyte, Dalia ^{[7
]}

Szewczyk, Magda ^{[7
]}

Hajian, Taraneh ^{[7
]}

Ibanez, Glorymar ^{[1
]}

Dong, Aiping ^{[7
]}

Dombrovski, Ludmila ^{[7
]}

Zhang, Zhenyu ^{[6
]}

Deng, Haiteng ^{[7
,11
]}

Min, Jinrong ^{[7
,12
]}

Arrowsmith, Cheryl H. ^{[7
,13
]}

Mazutis, Linas ^{[9
]}

Shi, Lei ^{[8
]}

Vedadi, Masoud ^{[7
,14
]}

Brown, Peter J. ^{[7
]}

Xiang, Jenny ^{[2
]}

Qin, Li-Xuan ^{[15
]}

Xu, Wei ^{[3
]}

Luo, Minkui ^{[1
,4
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Chem Biol Program, 1275 York Ave, New York, NY 10021 USA

[2] Cornell Univ, Genom Resources Core Facil, Weill Cornell Med Coll, New York, NY 10021 USA

[3] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA

[4] Cornell Univ, Program Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Triinst PhD Program Chem Biol, 1275 York Ave, New York, NY 10021 USA

[6] Capital Med Univ, Affiliat Hosp, Chaoyang Hosp, Dept Obstet & Gynecol, Beijing, Peoples R China

[7] Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada

[8] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA

[9] Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, 1275 York Ave, New York, NY 10021 USA

[10] Mem Sloan Kettering Canc Ctr, Triinst PhD Program Computat Biol & Med, 1275 York Ave, New York, NY 10021 USA

[11] Tsinghua Univ, Sch Life Sci, Ctr Synthet & Systemat Biol, Beijing, Peoples R China

[12] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[13] Univ Toronto, Dept Med Biophys, Princess Margaret Canc Ctr, Toronto, ON, Canada

[14] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada

[15] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

来源：

ELIFE | 2019年 / 8卷

基金：

美国国家卫生研究院;

关键词：

STRUCTURAL BASIS; SELECTIVE INHIBITOR; METHYLTRANSFERASE; ASSAY; METHYLATION; COMPLEX; DRUG; EZH2; REFINEMENT; LEUKEMIA;

D O I：

10.7554/eLife.47110

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：42

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