title: Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma.
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.
authors.affiliation: From the Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Huabo
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: From the Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Lia R
authors.initials: LR
authors.lastname: Edmunds
authors.affiliation: From the Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Sucheta
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: From the Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: James
authors.initials: J
authors.lastname: Dolezal
authors.affiliation: the Department of Pathology, the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15237.
authors.forename: Junyan
authors.initials: J
authors.lastname: Tao
authors.affiliation: the Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: the Division of Neonatology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Laura
authors.initials: L
authors.lastname: Jackson
authors.affiliation: From the Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Marc
authors.initials: M
authors.lastname: Fromherz
authors.affiliation: the Department of Cell Biology, the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15237.
authors.forename: Donna
authors.initials: D
authors.lastname: Beer-Stolz
authors.affiliation: the Division of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Radha
authors.initials: R
authors.lastname: Uppala
authors.affiliation: the Division of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Sivakama
authors.initials: S
authors.lastname: Bharathi
authors.affiliation: the Department of Pathology, the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15237.|the Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15237.
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
authors.affiliation: the Division of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Goetzman
authors.affiliation: From the Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, procev@chp.edu.|the Department of Microbiology and Molecular Genetics, the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15237, and.|the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Prochownik
mesh_terms: D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018197:Hepatoblastoma / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D000105:Acetyl Coenzyme A; D000255:Adenosine Triphosphate
keywords: Myc (c-Myc); beta-catenin (B-catenin); hepatocellular carcinoma; metabolism; oxidative phosphorylation; yes-associated protein (YAP)