Hepatic POLB served as a critical component for maintaining circadian homeostasis and was clinically overexpressed in the HCC patients, driving cancer progression through demethylation of the 4th CpG island on the 5′UTR of clock gene Per1. Our findings furnish key insights into the molecular mechanism that drives the synergistic effects of clock and food signals on the POLB-driven BER system, and uncover the novel clock-linked carcinogenic effects of POLB in the liver. This evidence concerns the gene POLB and cancer.