Liver cancer development driven by the AP-1/c-Jun~Fra2 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 AP-1 (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens 1 and 2 (Fra-1/2) 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-2hep 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-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis and Pparg-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently directly regulated 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 BET bromodomain inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a novel 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. Overall design: RNA from murine (adult males, C57BL/6) liver samples was sequenced. Two sets were included in the experiment in twosequencing runs: the first set included 9 samples from mice sacrificed 2 months after transgene induction in 6 controls and 3 mutants. The second set included 10 samples from mice sacrificed 9 months after transgene induction in 3 controls and 3 mutants. in the 3 mutants, 3 samples corresponded to areas that were macroscopically tumor free (periT) and 4 samples corresponded to macroscopically visible tumors: two tumors from mutant -1 and one tumor from each of mutant -2 and mutant-3. Comparative expression profiling was conducted across genotype (mutants compared to controls) and time. Transgene expression in the mutants was always started at weaning (3 weeks of age) by doxycycline removal. Controls were littermates that received the same treatment. Grant ID: 741888 (ERC AdG 2016) Grant title: CSI-Fun Funding source: European Research Council Grantee name: Erwin F.Wagner Grant ID: 859860 (ITN 2019) Grant title: CANCERPREV Funding source: H2020 - MSCA Grantee name: Erwin F. Wagner