title: Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling.
abstract: The tumor suppressor protein Merlin is proteasomally degraded in breast cancer. We undertook an untargeted metabolomics approach to discern the global metabolomics profile impacted by Merlin in breast cancer cells. We discerned specific changes in glutathione metabolites that uncovered novel facets of Merlin in impacting the cancer cell metabolome. Concordantly, Merlin loss increased oxidative stress causing aberrant activation of Hedgehog signaling. Abrogation of GLI-mediated transcription activity compromised the aggressive phenotype of Merlin-deficient cells indicating a clear dependence of cells on Hedgehog signaling. In breast tumor tissues, GLI1 expression enhanced tissue identification and discriminatory power of Merlin, cumulatively presenting a powerful substantiation of the relationship between these two proteins. We have uncovered, for the first time, details of the tumor cell metabolomic portrait modulated by Merlin, leading to activation of Hedgehog signaling. Importantly, inhibition of Hedgehog signaling offers an avenue to target the vulnerability of tumor cells with loss of Merlin.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Shamik
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Jeevan K
authors.initials: JK
authors.lastname: Prasain
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Hanna
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Bailey
authors.affiliation: University of South Alabama, AL 36617, United States.
authors.forename: J Allan
authors.initials: JA
authors.lastname: Tucker
authors.affiliation: Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.|Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Sejong
authors.initials: S
authors.lastname: Bae
authors.affiliation: Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Landon S
authors.initials: LS
authors.lastname: Wilson
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Samant
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.|Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Barnes
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Lalita A
authors.initials: LA
authors.lastname: Shevde
mesh_terms: D000222:Adaptation, Physiological; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D055442:Metabolome; D025581:Neurofibromin 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics / Q000378:metabolism
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D025581:Neurofibromin 2; D000071676:Zinc Finger Protein GLI1