Significance
Hepatocellular carcinoma (HCC) is a deadly cancer with limited treatment
options. The AP-1 transcription factor components c-Fos and c-Jun were
previously linked to HCC, but the role of Fra proteins was unclear. This
study establishes a new mouse model for HCC research and reveals that
hepatic expression of a c-Jun/Fra-2 dimer induces spontaneous tumors
with HCC features. Tumor growth is fueled by dysregulated cell cycle,
inflammation, dyslipidemia and increased c-Myc. Switching off
c-Jun~Fra-2 reverts tumor growth, whereas escaping
tumors maintain c-Myc, consistent with c-Jun/Fra-2-mediated regulation
of c-Myc driving HCC. Furthermore, blocking c-Myc using the BET
inhibitor JQ-1 halts tumor growth. The data suggest that the novel
c-Jun/Fra-2-Myc interaction is pertinent to future clinical studies
aimed at improving HCC patient care.