Prohibitin 1 is an evolutionary conserved and ubiquitously expressed protein that exerts different biological functions depending on its subcellular localization. The role of prohibitin 1 in liver cancer is controversial as it can be pro- or anti-tumorigenic. However, most of the studies to date have described prohibitin 1 primarily as a tumor suppressor in the liver. Its deficiency sensitizes the liver to cholestatic liver injury, non-alcoholic fatty liver disease, inflammatory insults, and cancer. Liver-specific Phb1-knockout mice spontaneously develop hepatocellular carcinoma, Phb1 heterozygotes are more susceptible to develop cholangiocarcinoma, and the majority of human hepatocellular carcinomas and cholangiocarcinomas have reduced prohibitin 1 expression. Consistent with a tumor suppressive role in the liver, prohibitin 1 negatively regulates proliferation in hepatocytes and human hepatocellular carcinoma and cholangiocarcinoma cell lines, and multiple oncogenic signaling pathways are activated when prohibitin 1 is deficient. Although best known as a mitochondrial chaperone, prohibitin 1 can protect the liver by mitochondrial-independent mechanisms. This review summarizes what’s known about prohibitin 1’s role in liver pathology, with the focus on hepatoprotection and carcinogenesis.
Impact statement: This review summarizes the last decades of research on PHB1 in liver pathobiology. PHB1 is a key player for liver health as it is hepatoprotective and tumor suppressive. We highlight the importance of PHB1’s subcellular localization, post-translational modifications, and interacting proteins as major determinants of PHB1 cytoprotective function and anti-tumor activity in the liver.
Keywords: Prohibitin; cholangiocarcinoma; cholestatic liver injury; hepatocellular carcinoma.