ATAD2B governs epigenetic silencing of the epithelial program to fuel cancer metastasis and neuronal migration

Epithelial-to-mesenchymal transition (EMT) is a pivotal developmental program that is frequently co-opted to drive cancer aggressiveness and metastasis. While the dynamic remodelling of histone H3 lysine 27 acetylation (H3K27ac) landscapes is a hallmark of EMT, the specific chromatin readers decoding these epigenetic signals remain largely unknown. Here, we identify ATAD2B as a novel H3K27ac reader essential for cell migration in both cancer metastasis and brain development. Multi-omics profiling revealed that, at EMT onset, ATAD2B targets H3K27ac at active epithelial identity genes via its bromodomain and recruits HDAC1 to epigenetically silence them, enforcing a mesenchymal state. ATAD2B loss impairs migration and invasion in breast cancer lines and Patient-Derived organoids, whereas its overexpression accelerates in vivo lung metastasis and correlates with poor patient survival. Furthermore, ATAD2B promotes the migration of newborn neurons in the developing brain. Our findings establish ATAD2B as a versatile chromatin reader orchestrating cell motility across development and disease.