Nopparat J, Zhang J, Lu J-P, Chen Y-H, Zheng D, Neufer P D, Fan J M, Hong H, Boykin C, Lu Q
Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
College of Life Sciences, Zhejiang University, Hangzhou, China.
Oncogene. 2015 Mar 19;34(12):1542-52. doi: 10.1038/onc.2014.89. Epub 2014 Apr 14.
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.
Wnt/β-连环蛋白信号通路的突变在发育和癌症中起着至关重要的作用。虽然β-连环蛋白和腺瘤性息肉病 coli（APC）基因突变已得到充分证实，并且已知会驱动肿瘤发生，但该信号通路其他成分的突变发现滞后，这阻碍了对癌症机制的理解。在此我们报告，δ-连环蛋白（基因命名：CTNND2）是β-连环蛋白超家族的主要神经成员，可促进经典Wnt/β-连环蛋白/淋巴样增强因子1（LEF-1）介导的转录，在人类前列腺癌中显示外显子突变，并促进癌细胞的生存适应和代谢重编程。当在源自前列腺肿瘤异种移植的细胞中过表达时，δ-连环蛋白基因总是会发生突变，导致序列中断，预示着功能改变。整合到宿主染色体中的异位δ-连环蛋白基因是非位点选择性的。δ-连环蛋白突变通过前列腺特异性表达原癌基因Myc的前列腺素启动子（ARR2PB）驱动，促进小鼠前列腺肿瘤的发展，而突变细胞在过度生长和葡萄糖剥夺时具有生存优势。能量利用重编程伴随着葡萄糖转运蛋白1和聚（ADP-核糖）聚合酶裂解的下调，同时保留肿瘤型2丙酮酸激酶的表达。δ-连环蛋白突变增加β-连环蛋白向细胞核的转位和缺氧诱导因子1α（HIF-1α）的表达。因此，引入δ-连环蛋白突变是前列腺癌代谢适应中的一个重要里程碑，它通过在葡萄糖短缺的情况下调节β-连环蛋白和HIF-1α信号通路来放大其促肿瘤潜能。
