Here, YEATS domain‐containing protein 4 (YEATS4) is an essential gene for BC cell viability using CRISPR‐Cas9 library screening is reported, and that HUWE1 is an E3 ligase responsible for YEATS4 ubiquitination and proteasomal degradation by the Protein Stability Regulators Screening Assay. This evidence concerns the gene YEATS4 and breast cancer.