Dr. Sungjin Ko and Dr. Paul Monga publish a study in Gastroenterology, entitled, “NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma.” Other PLRC members who contributed to the study include Dr. Silvia Liu, Dr. Aaron Bell, Dr. Michael Oertel, Dr. Reben Raeman, Dr. Kari Nejak-Bowen, Dr. Aatur Singhi and Dr. Jianhua Luo.
BACKGROUND AND AIM: Intrahepatic cholangiocarcinoma (ICC) is a devastating liver cancer with extremely high intra- and inter-tumoral molecular heterogeneity, partly due to its diverse cellular origins. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development. METHODS: Expression of ICC driver genes in human diseased livers at risk for ICC development were examined. Sleeping beauty and hydrodynamic tail vein injection based AktNICD/YAP1 ICC model was used to investigate pathogenetic roles of SOX9 and YAP1 in HC-driven ICC. We identify DNA methyltransferase-1 (DNMT1) as a YAP1 target, which was validated by loss- and gain-of-function studies, and its mechanism addressed by chromatin immunoprecipitation sequencing. RESULTS: Co-expression of AKT and NICD/YAP1 in HC yielded ICC which represent 16-30% of clinical ICC. NICD independently regulates SOX9 and YAP1 and deletion of either, significantly delays ICC development. Yap1 or TEAD inhibition, but not Sox9 deletion, impairs HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate-switch through the repression of HC-specific genes regulated by master regulators for HC differentiation including HNF4, HNF1 and CEBP/. DNMT1 loss prevented Notch/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development. CONCLUSION: We identify a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for of HC-to-BEC/ICC conversion, may be relevant in cholestasis-to-ICC pathogenesis in the clinic.