title: Bile acids activate YAP to promote liver carcinogenesis.
abstract: Elevated bile acid levels increase hepatocellular carcinoma by unknown mechanisms. Here, we show that mice with a severe defect in bile acid homeostasis due to the loss of the nuclear receptors FXR and SHP have enlarged livers, progenitor cell proliferation, and Yes-associated protein (YAP) activation and develop spontaneous liver tumorigenesis. This phenotype mirrors mice with loss of hippo kinases or overexpression of their downstream target, YAP. Bile acids act as upstream regulators of YAP via a pathway dependent on the induction of the scaffold protein IQGAP1. Patients with diverse biliary dysfunctions exhibit enhanced IQGAP1 and nuclear YAP expression. Our findings reveal an unexpected mechanism for bile acid regulation of liver growth and tumorigenesis via the Hippo pathway.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, IL 61801, USA. Electronic address: anakk@illinois.edu.
authors.forename: Sayeepriyadarshini
authors.initials: S
authors.lastname: Anakk
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, IL 61801, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhosale
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry and Molecular Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: moore@bcm.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics; D000090683:Hippo Signaling Pathway; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001647:Bile Acids and Salts; D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D020703:ras GTPase-Activating Proteins; D000099150:Receptor, Farnesoid X-Activated; C101203:IQ motif containing GTPase activating protein 1; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; C082332:macrophage stimulating protein; C099713:nuclear receptor subfamily 0, group B, member 2; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases