Crotonate suppresses breast cancer metastasis and promotes immunotherapy response by inducing ACSS2-mediated EZH2-K348 crotonylation

TL;DR

Crotonate, a short-chain fatty acid, can reduce breast cancer growth and improve immunotherapy by causing the breakdown of the EZH2 protein.

Contribution

Crotonate induces EZH2-K348 crotonylation, leading to its degradation and suppression of breast cancer.

Findings

Crotonate promotes EZH2 degradation via K348 crotonylation.

Crotonate inhibits breast cancer growth and metastasis more effectively than tazemetostat.

Crotonate combined with anti-PD-L1 improves immunotherapy response in breast cancer.

Abstract

Crotonate, a short-chain fatty acid, generates protein crotonylation. However, the role of crotonate in cancer progression is unknown. Here, we present a crotonate–crotonyl–coenzyme A (CoA)–enhancer of zeste homolog 2 (EZH2) crotonylation cascade blocking breast cancer growth and metastasis. We demonstrated that crotonate promotes EZH2 degradation via crotonyl-CoA–mediated crotonylation at Lys348 in EZH2 (EZH2-K348cr). EZH2-K348cr leads to reduced genome-wide H3K27me3 (trimethylation of lysine-27 on histone-3) occupancy. Crotonate metabolizes to crotonyl-CoA by ACSS2 (acyl-CoA synthetase 2), and then, acyltransferase p300 catalyzes crotonyl-CoA and generates EZH2-K348cr. Crotonylated EZH2 triggers EZH2 ubiquitination and degradation. Administration of crotonate markedly inhibits breast cancer cell growth and metastasis via a crotonate-crotonyl-CoA-EZH2-K348cr cascade. In comparison, crotonate showed better blocking effect than EZH2 inhibitor tazemetostat in suppressing breast cancer metastasis. The combination of crotonate and anti-PD-L1 (programmed cell death ligand 1) antibody enhances responses of breast cancer cells to immunotherapy. Together, our findings indicate that crotonate is a promising anticancer drug candidate that suppresses breast cancer growth and metastasis by specifically inducing EZH2 degradation.

Short-chain fatty acid crotonate is a possible breast cancer killer through inducing the degradation of oncogenic protein EZH2.

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