Loss of PHRF1 impairs the migration and invasion in murine hepatocellular carcinomas by modulating the expression of CEBPA
PHRF1 (PHD and ring finger domains 1) is an E3 ubiquitin ligase with multiple functions involved in TGF-b signaling, non-homologous end-joining (NHEJ), and invasion potential of cancer cells. However, its function in liver tumorigenesis remains unclear. To investigate the role of PHRF1 ablation in hepatocellular carcinoma (HCC) progression, we crossed PHRF1fl/fl mice with Albumin (Alb)-Cre_KrasLSL-G12D_p53fl/fl (KP) mice to generate liver-specific Alb-cre_KrasLSL-G12D_p53fl/fl_PHRF1fl/fl (KPP) mice, which spontaneously developed liver cancers as early as 16-20 weeks after birth. PHRF1 ablation delayed the occurrence of liver cancers and prolonged overall survival compared with PHRF1-proficient and heterozygous mice. Wound-healing and transwell invasion assays showed markedly reduced migratory and invasive capacities in PHRF1-deficient HCC cells. Mechanistically, transcriptomic and biochemical analyses indicated that CEBPA is a potential downstream mediator of PHRF1. Functional studies demonstrated that ectopic expression of CEBPA restored migration and invasion in PHRF1-deficient KPP cells, whereas depletion of CEBPA impaired these phenotypes in KP cells. Collectively, our findings identify a previously unrecognized oncogenic role for PHRF1 in HCC and demonstrate that the PHRF1-CEBPA axis may play an important role in tumor progression by enhancing cancer cell motility and invasiveness.