We demonstrated that in breast cancer cells, CXXC5 is responsible for initiating the transcriptional repression of TSC1, followed by monoubiquitination of H2AK119 by the CRL4B complex and NuRD (MTA1) complex–mediated histone deacetylation, which create a repressive chromatin environment. Here, CXXC5 is linked to breast carcinoma.