β-catenin-cohesin ring-CEGRs/ALCDs axis activation contributes to the development of hepatoblastoma and fibrolamellar HCC

Abstract The pediatric and adolescent liver cancers Hepatoblastoma (HBL) and Fibrolamellar hepatocellular carcinoma (FLC) are dangerous diseases requiring aggressive surgery, when feasible, and non-targeted toxic chemotherapy for a chance of cure, due to insufficient knowledge of underlying molecular mechanisms. We’ve previously reported the essential role of ph-S675-β-catenin in the reorganization of genomic structure in HBL and FLC by oncogenic activation via chromosomal regions called Cancer Enhancing Genomic Regions or Aggressive Liver Cancer Domains (CEGRs/ALCDs). In FLC, the fusion J-PKAc oncoprotein phosphorylates β-catenin at Ser675, triggering such CEGRs/ALCDs-mediated activation of oncogenes. In this paper, we found that all members of the cohesin ring - CTCF, Rad21, SMC1, SMC3 and STAG1 - and β-catenin-TCF4 are bound to CEGRs/ALCDs of oncogenes in HBL and FLC, as well as many other cancers, and that this binding increases transcription. Examination of a large cohort of HBL and FLC samples revealed that cohesin ring expression is dramatically elevated in the majority. The cohesin ring, as well as the ph-S675-β-catenin-TCF4-p300 complex, are detected on both the promoter and intron-located CEGRs/ALCDs of NRF2 and Thy1, correlating with increased transcription. This suggests that the cohesin ring creates the DNA-loop for oncogene activation. The inhibition of the cohesin ring by JQ1 reduces proliferation of HBL and FLC cells in culture, as well as cells expressing the FLC-specific DNAJB1-PKAc fusion oncogene. Implications: These studies provide evidence that J-PKAc-β-catenin and the cohesin ring cooperate in oncogenic activation for both HBL and FLC.