Irf3 and Irf7 induce epigenetic changes to promote pancreatic carcinogenesis
Recommended Citation
Fahr L, Benitz S, Schreiner N, Straub T, Mutter J, Hamidach H, Mahajan UM, Beyer G, Steiger K, Terrasi A, Schotta G, Imhof A, Lauber K, Kleeff J, Michalski CW, Mayerle J, Regel I. Irf3 and Irf7 induce epigenetic changes to promote pancreatic carcinogenesis. Pancreatology 2024; 24:e116-e117.
Document Type
Conference Proceeding
Publication Date
12-5-2024
Publication Title
Pancreatology
Abstract
The interferon regulatory factors 3 and 7 (Irf3, Irf7) are transcription factors downstream of the TLR3 pathway. We discovered an overexpression of Tlr3, Irf3 and Irf7 in pancreatic acinar-to-ductal metaplasia (ADM) and tumor cells. Furthermore, ADM and tumor cells exhibit epigenetic modifications, including changes in chromatin accessibility of interferon-response genes. Own preliminary data show that Irf3/Irf7 depletion prevents tumor development in the pancreas in an inducible oncogenic Kras mouse model. In this study, we want to investigate whether Irf3/Irf7-deficient ADM and pancreatic tumor cells lack an epigenetic tumor-promoting program which is essential for pancreatic tumorigenesis. Immunoblot and immunohistochemistry staining were used to detect changes in total histone modification levels in cerulein-treated Irf3/Irf7 knockout mice expressing an inducible Kras mutation. 3D-ADM cultures were performed to assess reprogramming abilities of Irf3/Irf7KO acinar cells. Moreover, we created Irf3/Irf7KO mouse tumor cells with CRISPR/Cas9 to determine changes in tumor cell characteristics. Tumor formation capabilities were tested in orthotopic and metastatic mouse models. Possible alterations of an epigenetic, tumor-promoting program were analyzed by RNA-seq, ATAC-seq and ChIP-seq for H3K27ac and H3K4me3 in Irf3/Irf7KO tumor cells. Cerulein treatment of inducible oncogenic Kras mice lacking Irf3/Irf7 results in ADM formation without further development of precursor lesions or tumors. Irf3/Irf7KO acinar cells exhibit reduced reprogramming abilities in 3D culture. Furthermore, the tumorigenic potential of Irf3/Irf7KO tumor cells is strongly reduced in vivo, with no tumor growth in an orthotopic and metastatic mouse model. Moreover, Irf3/Irf7KO tumor cells show a significantly less aggressive phenotype in vitro with decreased colony and sphere formation capacities and reduced invasive potential. Depletion of Irf3/Irf7 in tumor cells leads to decreased H3K27ac and higher H3K4me3 levels as well as increased expression and activity of histone deacetylases 1 and 2. Downregulated genes in Irf3/7KO ADM and tumor cells are associated with tumor-promoting programs such as migration, mitochondrial respiration and chromatin organization. Our findings indicate that the transcription factors Irf3 and Irf7 play a significant role in establishing an epigenetic signature that gives rise to an aggressive phenotype of the tumor cells and supports a tumor-promoting program.
Volume
24
First Page
e116
Last Page
e117
