These results thus demonstrate that downregulation of Sam68 lessens colon tumor development in Apcmin716/+ mice and sensitizes human colon cancer cells to genotoxic stress-induced apoptosis, in line with the indispensible role of Sam68 in the nuclear-initiated PARylation, NF-κB activation, and anti-apoptotic transcription in mouse and human colon cancer cells. Here, KHDRBS1 is linked to malignant colon neoplasm.