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 play 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 which 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 gave rise to mutations leading to sequence disruptions predicting functional alterations. Ectopic δ-catenin gene integrating into host chromosomes is locus non-selective. δ-Catenin mutations promote tumor development in mouse prostate with probasin promoter (ARR2PB)-driven, prostate-specific expression of myc oncogene, while mutant cells empower survival advantage upon overgrowth and glucose deprivation. Reprogramming energy utilization accompanies the down-regulation of glucose transporter-1 (Glut-1) and Poly (ADP-ribose) polymerase (PARP) cleavage while preserving tumor type 2 pyruvate kinase (PKM2) expression. δ-Catenin mutations increased β-catenin translocation to the nucleus and 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.

Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST

“…This gene is expressed in normal brain and is commonly overexpressed in several cancers. However, several somatic frameshift mutations are recorded in the COSMIC database, and loss-of-function mutations were identified in glioblastoma and pancreatic adenocarcinoma (31,42). Moreover, in the same patients, several chromosomal rearrangements were detected that lead to premature stop of relevant genes, such as TET1 and SPRED2.…”

Genetic alterations of δ-catenin/NPRAP/Neurojungin (CTNND2): functional implications in complex human diseases

“…In addition, CWR22-Rv1 cells with truncated δ-catenin tolerated glucose starvation. Altogether, these findings highlight the ability of cancer cells to alter genes resulting in increased cancer cell survival and/or transformation along with modifying cellular metabolism (Nopparat et al 2015). …”

“…More recently, gene variations were observed after sequencing and analyzing the entire coding region of δ-catenin from a total of 24 out of 40 human prostatic adenocarcinomas (Nopparat et al 2015). Most functional mutations occurred after exon 9 while missense or frameshifting mutations occurred after exon 13.…”

“…For example, δ-catenin is amplified in esophageal carcinoma cell lines that show increased Wnt signaling (Brown et al 2011). δ-Catenin mutations alter protein expression and distribution in the Wnt/β-catenin and hypoxia pathways (Nopparat et al 2015). Radiation hybrid mapping of genes in the lithium-sensitive Wnt signaling pathway included Wnt, frizzled, disheveled, GSK-3α/β, axin, α-catenin, δ-catenin and ARVCF, and a frizzled-like protein (frpHE) on human chromosomes (Rhoads et al 1999).…”

Genetically Engineered Mouse Models of Prostate Cancer in the Postgenomic Era

“…In particular, GEMMs based on conditional loss of function of Apc in prostate develop high-grade PIN or adenocarcinoma, depending on the Cre driver, and collaborate with gain of expression of Hepsin in cancer progression (Bruxvoort et al 2007;Valkenburg et al 2014Valkenburg et al , 2015. Correspondingly, GEMMs based on conditional activation of βcatenin display PIN phenotypes, which have accelerated cancer progression in collaboration with loss of function of Pten, gain of expression of Myc, or activation of Kras, or in the context of the LADY transgenic model, which expresses the SV40 T-antigen under the control of the large Probasin promoter (Box 2) (Kasper et al 1998;Pearson et al 2009;Yu et al 2009Yu et al , 2011Francis et al 2013;Nopparat et al 2015).…”