Here, we demonstrate that acetylation of YEATS4 by the histone acetyltransferase KAT8 stabilizes YEATS4 via impairing its binding to E3 ligase HUWE1 and promotes BC tumor growth and that targeting the KAT8/YEATS4 axis suppresses tumor growth and sensitizes BC cells to cisplatin. Here, HUWE1 is linked to breast cancer.