title: δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming.
abstract: Mutations of Wnt/β-catenin signaling pathway has essential roles in development and cancer. Although β-catenin and adenomatous polyposis coli (APC) gene mutations are well established and are known to drive tumorigenesis, discoveries of mutations in other components of the pathway lagged, which hinders the understanding of cancer mechanisms. Here we report that δ-catenin (gene designation: CTNND2), a primarily neural member of the β-catenin superfamily that promotes canonical Wnt/β-catenin/LEF-1-mediated transcription, displays exonic mutations in human prostate cancer and promotes cancer cell survival adaptation and metabolic reprogramming. When overexpressed in cells derived from prostate tumor xenografts, δ-catenin gene invariably gives rise to mutations, leading to sequence disruptions predicting functional alterations. Ectopic δ-catenin gene integrating into host chromosomes is locus nonselective. δ-Catenin mutations promote tumor development in mouse prostate with probasin promoter (ARR2PB)-driven, prostate-specific expression of Myc oncogene, whereas mutant cells empower survival advantage upon overgrowth and glucose deprivation. Reprogramming energy utilization accompanies the downregulation of glucose transporter-1 and poly (ADP-ribose) polymerase cleavage while preserving tumor type 2 pyruvate kinase expression. δ-Catenin mutations increase β-catenin translocation to the nucleus and hypoxia-inducible factor 1α (HIF-1α) expression. Therefore, introducing δ-catenin mutations is an important milestone in prostate cancer metabolic adaptation by modulating β-catenin and HIF-1α signaling under glucose shortage to amplify its tumor-promoting potential.
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nopparat
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: J-P
authors.initials: JP
authors.lastname: Lu
authors.affiliation: 1] Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA [2] Leo Jenkins Cancer Center, The Brody School of Medicine, East Carolina University, Greenville, NC, USA [3] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Chen
authors.affiliation: 1] Department of Kinesiology, East Carolina University, Greenville, NC, USA [2] East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zheng
authors.affiliation: 1] Department of Kinesiology, East Carolina University, Greenville, NC, USA [2] East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA [3] Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Neufer
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Fan
authors.affiliation: Department of Pathology and Laboratory Medicine, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Boykin
authors.affiliation: 1] Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA [2] Leo Jenkins Cancer Center, The Brody School of Medicine, East Carolina University, Greenville, NC, USA [3] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000818:Animals; D051177:Catenins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D051177:Catenins; D051176:beta Catenin; D005947:Glucose; D000095002:Delta Catenin
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