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

TY - JOUR

T1 - Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc

AU - Bakiri, Latifa

AU - Hasenfuss, Sebastian C.

AU - Guío-Carrión, Ana

AU - Thomsen, Martin K.

AU - Hasselblatt, Peter

AU - Wagner, Erwin F.

PY - 2024/4

Y1 - 2024/4

N2 - 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-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 Ppar?-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 Extra-Terminal motif 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 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.

AB - 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-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 Ppar?-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 Extra-Terminal motif 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 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.

KW - AP-1

KW - c-Jun/Fra-2

KW - c-Myc

KW - HCC

KW - mouse models

KW - Humans

KW - Protein Multimerization

KW - Gene Expression Regulation, Neoplastic

KW - Mice, Transgenic

KW - Proto-Oncogene Proteins c-myc/metabolism

KW - Fos-Related Antigen-2/metabolism

KW - Transcription Factor AP-1/metabolism

KW - Proto-Oncogene Proteins c-jun/metabolism

KW - Animals

KW - Hepatocytes/metabolism

KW - Proto-Oncogene Proteins c-fos/metabolism

KW - Carcinoma, Hepatocellular/metabolism

KW - Mice

KW - Liver Neoplasms/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85191376652&partnerID=8YFLogxK

U2 - 10.1073/pnas.2404188121

DO - 10.1073/pnas.2404188121

M3 - Journal article

C2 - 38657045

AN - SCOPUS:85191376652

SN - 0027-8424

VL - 121

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

IS - 18

M1 - e2404188121

ER -