Timeframe: 2020 – 2021
Goal: Document mechanisms driving FLC and test if treatment with inhibitors of b-catenin may be a potential therapeutic approach for FLC
Principal Investigator: Nikolai Timchenko, PhD, Head of Liver Tumor Biology, Liver Tumor Program; Professor, UC Department of Surgery
In the course of studies of pediatric liver cancer, we have identified chromosomal regions (Aggressive Liver Cancer Domains, ALCDs) in multiple liver cancer genes. Expression of the ALCD containing genes is increased in liver cancer. The project team identified several regions within ALCDs that might be activated by transcription factors and chromatin remodeling proteins. One of these regions contains an ideal binding site for b-catenin-TCF4 complexes. Given recent reports showing that the mutant kinase DNAJB1-PKAc phosphorylates b-catenin, they hypothesized that DNAJB1-PKAc activates ALCD-containing cancer genes leading to FLC pathology. Preliminary studies of FLC patient tumor samples show that the DNAJB1-PKAc phosphorylates b-catenin at Ser675 leading to the formation of -catenin-TCF4 complexes and that these complexes bind to the ALCDs. They also identified the ALCD-containing cancer genes that are specifically upregulated in patients with FLC.
Therefore, the main hypothesis investigated in this effort is that DNAJB1-PKAc-b-catenin-ALCD axis plays a critical role in development of FLC. They:
- Examined if the DNAJB1-PKAc-b-catenin-TCF4 pathway activates known ALCD-dependent cancer genes in FLC patients
- Investigated new, FLC-specific ALCD-containing genes in FLC patients and determine mechanisms by which DNAJB1-PKAc-b-catenin pathway activates expression of these genes
- Examined if the inhibition of the DNAJB1-PKAc-b-catenin-TCF4 pathway by b-catenin inhibitor PRI-724 inhibits development of FLC in a mouse model of FLC.
The project aimed to provide critical knowledge of the mechanisms of FLC and test if treatments with inhibitors of b-catenin might be considered a potential therapeutic approach for FLC.