Liver cancer development driven by the AP-1/c- Jun∼Fra-2 dimer through c- Myc

Hepatocellular carcinoma (HCC) is a leading cause of cancer - related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein - 1 (AP - 1) (Fos/Jun) transcription factor family members c - Fos and c - Jun in HCC formation, the contribution of Fos - related antigens (Fra - ) 1 and 2 is unknown. Here, we show that hepatocyte - restricted expression of a single chain c - Jun - Fra - 2 protein, which functionally mimics the c - Jun/Fra - 2 AP - 1 dimer, results in spontaneous HCC formation in c - Jun - Fra - 2 hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c - Jun - Fra - 2 hep mice. Tumorigenesis occurs in the context of mild inflammation, low - grade fibrosis, and Ppar gamma- driven dyslipidemia. Subsequent analyses revealed increased expression of c - Myc, evidently under direct regulation by AP - 1 through a conserved distal 3 ' enhancer. Importantly, c - Jun - Fra - 2 - induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c - Jun - Fra - 2 transgene. Tumors escaping reversion maintained c - Myc and c - Myc target gene expression, likely due to increased c - Fos. Interfering with c - Myc in established tumors using the Bromodomain and ExtraTerminal motif inhibitor JQ - 1 diminished liver tumor growth in c - Jun - Fra - 2 mutant mice. Thus, our data establish c - Jun - Fra - 2 hep mice as a model to study liver tumorigenesis and identify the c - Jun/Fra - 2 - Myc interaction as a potential target to improve HCC patient stratification and/or therapy.