By integrating analysis of CUT&Tag and RNA sequencing data, we identified ubiquitin-specific protease 5 (USP5) as a Notch-signaling downstream effector that is transcriptionally upregulated by the NOTCH1 intracellular domain (NICD1)–RBPJ complex and mediates tumor angiogenesis. The gene discussed is CUX1; the disease is neoplasm.