Download MendeleyA chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.
Cai, X.C., Zhang, T., Kim, E.J., Jiang, M., Wang, K., Wang, J., Chen, S., Zhang, N., Wu, H., Li, F., Dela Sena, C.C., Zeng, H., Vivcharuk, V., Niu, X., Zheng, W., Lee, J.P., Chen, Y., Barsyte, D., Szewczyk, M., Hajian, T., Ibanez, G., Dong, A., Dombrovski, L., Zhang, Z., Deng, H., Min, J., Arrowsmith, C.H., Mazutis, L., Shi, L., Vedadi, M., Brown, P.J., Xiang, J., Qin, L.X., Xu, W., Luo, M.(2019) Elife 8
- PubMed: 31657716
- DOI: https://doi.org/10.7554/eLife.47110
- Primary Citation of Related Structures:
4IKP, 6D2L - PubMed 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.
Organizational Affiliation:
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
