Cell Chemical Biology
Volume 29, Issue 3, 17 March 2022, Pages 530-537.e7
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Brief Communication
Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6

https://doi.org/10.1016/j.chembiol.2021.07.012Get rights and content
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Highlights

  • Protein acyltransferase ZDHHC6 is a direct target of artemisinin in cancer cells

  • Artemisinin binds ZDHHC6 and inhibits its enzymatic activity

  • Artemisinin-mediated ZDHHC6 inhibition reduces NRas palmitoylation

  • Artemisinin disrupts the Golgi localization and signaling cascade of NRas

Summary

Protein S-palmitoylation is a post-translational modification that plays a crucial role in cancer cells by regulating the function and localization of oncoproteins and tumor suppressor proteins. Here, we identify artemisinin (ART), a clinically approved antimalarial endoperoxide natural product with promising anticancer activities, as an inhibitor of the ER-residing palmitoyl transferase ZDHHC6 in cancer cells using a chemoproteomic approach. We show that ART covalently binds and inhibits ZDHHC6 to reduce palmitoylation of the oncogenic protein NRas, disrupt NRas subcellular localization, and attenuate the downstream pro-proliferative signaling cascades. Our study identifies artemisinin as a non-lipid-based palmitoylation inhibitor targeting a specific palmitoyl acyltransferase and provides valuable mechanistic insights into the anticancer activity of artemisinins that are currently being studied in human clinical trials for different cancers.

Keywords

chemical proteomics
protein palmitoylation
natural products
artemisinin
Ras

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