δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming.
δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming.
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Wnt/β-catenin信号通路的突变在发育和癌症中起重要作用。虽然β-连环蛋白和腺瘤性结肠息肉病（APC）基因突变已得到充分证实，并已知会驱动肿瘤发生，但该途径其他组分中突变的发现滞后，这阻碍了对癌症机制的理解。在这里，我们报告了δ-catenin（基因命名：CTNND 2），β-catenin超家族的主要神经成员，促进经典Wnt/β-catenin/LEF-1介导的转录，在人前列腺癌中显示外显子突变，并促进癌细胞生存适应和代谢重编程。当在前列腺肿瘤异种移植物来源的细胞中过表达时，δ-连环蛋白基因总是引起突变，导致序列破坏，预测功能改变。外源δ-catenin基因整合到宿主染色体上具有位点非选择性。δ-连环蛋白突变通过probasin启动子（ARR 2 PB）驱动的myc癌基因的前列腺特异性表达促进小鼠前列腺中的肿瘤发展，而突变细胞在过度生长和葡萄糖剥夺时赋予生存优势。重编程能量利用伴随着葡萄糖转运蛋白-1（Glut-1）和聚（ADP-核糖）聚合酶（PARP）裂解的下调，同时保留肿瘤2型丙酮酸激酶（PKM 2）表达。δ-Catenin突变增加了β-catenin向细胞核的移位和HIF-1α的表达。因此，引入δ-catenin突变是前列腺癌代谢适应的重要里程碑，通过在葡萄糖缺乏下调节β-catenin和HIF-1α信号传导以放大其促肿瘤潜力。
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.
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