A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion. Academic Article uri icon

Overview

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.

authors

  • Cai, Xiao-Chuan
  • Zhang, Tuo
  • Kim, Eui-Jun
  • Jiang, Ming
  • Wang, Ke
  • Wang, Junyi
  • Chen, Shi
  • Zhang, Nawei
  • Wu, Hong
  • Li, Fengling
  • Dela Seña, Carlo C
  • Zeng, Hong
  • Vivcharuk, Victor
  • Niu, Xiang
  • Zheng, Weihong
  • Lee, Jonghan P
  • Chen, Yuling
  • Barsyte, Dalia
  • Szewczyk, Magda
  • Hajian, Taraneh
  • Ibáñez, Glorymar
  • Dong, Aiping
  • Dombrovski, Ludmila
  • Zhang, Zhenyu
  • Deng, Haiteng
  • Min, Jinrong
  • Arrowsmith, Cheryl H
  • Mazutis, Linas
  • Shi, Lei
  • Vedadi, Masoud
  • Brown, Peter J
  • Xiang, Jenny Zhaoying
  • Qin, Li-Xuan
  • Xu, Wei
  • Luo, Minkui

publication date

  • October 28, 2019

Research

keywords

  • Breast Neoplasms
  • Enzyme Inhibitors
  • Epigenesis, Genetic
  • Epigenomics
  • Protein-Arginine N-Methyltransferases

Identity

PubMed Central ID

  • PMC6917500

Scopus Document Identifier

  • 85075811499

Digital Object Identifier (DOI)

  • 10.1021/ja307060p

PubMed ID

  • 31657716

Additional Document Info

volume

  • 8