Abstract
Hepatoblastoma (HB) is associated with aberrant activation of the β-catenin and Hippo/YAP signaling pathways. Overexpression of mutant β-catenin and YAP in mice induces HBs that express high levels of c-Myc (Myc). In light of recent observations that Myc is unnecessary for long-term hepatocyte proliferation, we have now examined its role in HB pathogenesis using the above model. Although Myc was found to be dispensable for in vivo HB initiation, it was necessary to sustain rapid tumor growth. Gene expression profiling identified key molecular differences between myc+/+ (WT) and myc-/- (KO) hepatocytes and HBs that explain these behaviors. In HBs, these included both Myc-dependent and Myc-independent increases in families of transcripts encoding ribosomal proteins, non-structural factors affecting ribosome assembly and function, and enzymes catalyzing glycolysis and lipid bio-synthesis. In contrast, transcripts encoding enzymes involved in fatty acid β-oxidation were mostly down-regulated. Myc-independent metabolic changes associated with HBs included dramatic reductions in mitochondrial mass and oxidative function, increases in ATP content and pyruvate dehydrogenase activity, and marked inhibition of fatty acid β-oxidation (FAO). Myc-dependent metabolic changes included higher levels of neutral lipid and acetyl-CoA in WT tumors. The latter correlated with higher histone H3 acetylation. Collectively, our results indicate that the role of Myc in HB pathogenesis is to impose mutually dependent changes in gene expression and metabolic reprogramming that are unattainable in non-transformed cells and that cooperate to maximize tumor growth.
Highlights
Hepatoblastoma (HB) is associated with aberrant activation of the -catenin and Hippo/Yes-associated protein (YAP) signaling pathways
Myc-independent metabolic changes associated with HBs included dramatic reductions in mitochondrial mass and oxidative function, increases in ATP content and pyruvate dehydrogenase activity, and marked inhibition of fatty acid -oxidation (FAO)
familial adenomatous polyposis (FAP) is often associated with inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, which encodes a critical component of the Wnt/catenin signaling pathway [5]
Summary
Hepatoblastoma (HB) is associated with aberrant activation of the -catenin and Hippo/YAP signaling pathways. Global myc loss is embryonic lethal [24], whereas chronic Myc inhibition in adult mice is associated with long-term survival and only mild and reversible toxicities [25] Consistent with this latter finding, we have shown Myc to be dispensable for the ability of hepatocytes to replicate 50 –100-fold and repopulate the diseased liver in a murine model of hereditary tyrosinemia [26]. In this latter context, mycϪ/Ϫ (KO) hepatocytes showed modestly lower expression of ϳ15% of transcripts encoding 40S and 60S ribosomal subunit proteins, a tendency to be more reliant on fatty acid oxidation as an energy source following fasting and a propensity to accumulate intracellular neutral lipid. This role involves coordinating and maximizing ribosomal biogenesis, glycolysis, and lipid metabolism to keep space with increased biosynthetic needs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
