CUX1 is involved in transcription, DNA damage repair, proliferation, and differentiation. One target gene of CUX1 is PIK3IP1, which inhibits PI3K activity [ref. 17, ref. 18**]. Loss of CUX1 results in decreased PIK3IP1 expression and increased PI3K-AKT signaling, promoting proliferation and resembling the “Sustained proliferative signaling” Hallmark of Cancer [ref. 114]. CUX1 also downregulates expression of CFLAR, an anti-apoptotic protein that inhibits caspase-8 [ref. 18**]. Loss of CUX1 results in alleviation of CFLAR repression and apoptosis resistance, promoting the hallmark “Resisting cell death” [ref. 114]. CUX1 also regulates epigenetic histone marks and functions in epigenetic-driven DNA repair; CUX1 loss results in sustained DNA damage, resembling the hallmark “Genomic instability” [ref. 114]. CUX1 loss also results in ineffective erythropoiesis and impaired differentiation, though the mechanism remains unknown [ref. 17, ref. 18**]. CUX1 is depicted alone on the DNA strand for simplicity.