SBNO1 is an essential epigenetic driver with common and distinct roles in HCC and CCA

Background Aberrant Notch signaling is a potential driver of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Genetic studies in Drosophila showed that the strawberry notch (sno) knockout mimics loss of Notch and thus, we elucidated the role of the mammalian Strawberry Notch 1 (SBNO1) in HCC and CCA development.

Methods HCC and CCA gene expression and proteomics datasets were analyzed for SBNO1 expression. Tissue microarrays were immunohistochemically evaluated for SBNO1 protein expression. SBNO1 was downregulated using siRNA or sgRNA in cell lines followed by cell viability, colony formation and migration assays and gene expression analysis. To identify SBNO1 protein interaction partners, BioID was performed. Syngeneic mouse models using Hep55.1C cells and hydrodynamic tail vein injection (HDTV) were applied.

Results SBNO1 protein but not mRNA was significantly increased in HCC and CCA and SBNO1 protein localized to the nucleus suggesting a role in gene regulation. SBNO1-inhibition reduced cell viability, colony formation and migration. SBNO1-knockdown induced distinct expression patterns in HCC and CCA cell lines, however, BioID revealed that SBNO1 similarly modulates gene regulation in HCC and CCA by binding to general transcription factors TAF4 and TAF3. Sbno1 knockout in Hep55.1C reduced tumor growth in vivo and inhibited liver tumor development in three different models of HCC and CCA using HDTV. Furthermore, Sbno1-deletion reduced biliary differentiation and angiogenesis in the tumor margin indicating that Sbno1 is necessary for Notch-driven CCA formation.

Conclusions We identified SBNO1 as a new epigenetic driver required for HCC and iCCA tumor cell proliferation in vitro and in vivo.

Publication History

Article published online:
23 January 2024