Bile Acids Activate YAP to Promote Liver Carcinogenesis

Sayeepriyadarshini Anakk; Manoj Bhosale; Valentina A. Schmidt; Randy L. Johnson; Milton J. Finegold; David D. Moore

doi:10.1016/j.celrep.2013.10.030

Bile Acids Activate YAP to Promote Liver Carcinogenesis

Sayeepriyadarshini Anakk, Manoj Bhosale, Valentina A. Schmidt, Randy L. Johnson, Milton J. Finegold, David D. Moore

Research output: Contribution to journal › Article › peer-review

141 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1060-1069
Number of pages	10
Journal	Cell Reports
Volume	5
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2013.10.030
State	Published - Nov 27 2013

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Functional Proteomics Reverse Phase Protein Array Core

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10.1016/j.celrep.2013.10.030

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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.",

author = "Sayeepriyadarshini Anakk and Manoj Bhosale and Schmidt, {Valentina A.} and Johnson, {Randy L.} and Finegold, {Milton J.} and Moore, {David D.}",

note = "Funding Information: The authors would like to thank the NIDDK, Digestive Disease Center Morphology Core DK56338 (Houston, TX), especially Ms. Angela Major, for help with immunohistochemistry. We would also like to thank the proteomics core at UT MD Anderson Cancer Center funded by NCI grant CA16672. This study was supported by grants DK068804, DK62434, and CPRIT RP120138 (to D.D.M.), the R.P. Doherty, Jr. Welch Chair in Science (to D.D.M.), HD060579 (to R.L.J.), American Cancer Society Research Scholar grant RSG-09-033-01-CSM (to V.A.S.), and start-up funds from the University of Illinois at Urbana-Champaign (to S.A.). ",

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AU - Anakk, Sayeepriyadarshini

AU - Bhosale, Manoj

AU - Schmidt, Valentina A.

AU - Johnson, Randy L.

AU - Finegold, Milton J.

AU - Moore, David D.

N1 - Funding Information: The authors would like to thank the NIDDK, Digestive Disease Center Morphology Core DK56338 (Houston, TX), especially Ms. Angela Major, for help with immunohistochemistry. We would also like to thank the proteomics core at UT MD Anderson Cancer Center funded by NCI grant CA16672. This study was supported by grants DK068804, DK62434, and CPRIT RP120138 (to D.D.M.), the R.P. Doherty, Jr. Welch Chair in Science (to D.D.M.), HD060579 (to R.L.J.), American Cancer Society Research Scholar grant RSG-09-033-01-CSM (to V.A.S.), and start-up funds from the University of Illinois at Urbana-Champaign (to S.A.).

PY - 2013/11/27

Y1 - 2013/11/27

N2 - 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.

AB - 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.

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Bile Acids Activate YAP to Promote Liver Carcinogenesis

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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