ARC Special Research Centre for the Molecular Genetics of Development and Discipline of Genetics, School ofMolecular and Biomedical Sciences, The University of Adelaide, Adelaide S.A. 5005, Australia.
Hum Mol Genet. 2011 Feb 1;20(3):497-509. doi: 10.1093/hmg/ddq495. Epub 2010 Nov 12.
Common chromosomal fragile sites FRA3B and FRA16D are frequent sites of DNA instability in cancer, but their contribution to cancer cell biology is not yet understood. Genes that span these sites (FHIT and WWOX, respectively) are often perturbed (either increased or decreased) in cancer cells and both are able to suppress tumour growth. While WWOX has some tumour suppressor characteristics, its normal role and functional contribution to cancer has not been fully determined. We find that a significant proportion of Drosophila Wwox interactors identified by proteomics and microarray analyses have roles in aerobic metabolism. Functional relationships between Wwox and either CG6439/isocitrate dehydrogenase (Idh) or Cu-Zn superoxide dismutase (Sod) were confirmed by genetic interactions. In addition, altered levels of Wwox resulted in altered levels of endogenous reactive oxygen species. Wwox (like FHIT) contributes to pathways involving aerobic metabolism and oxidative stress, providing an explanation for the 'non-classical tumour suppressor' behaviour of WWOX. Fragile sites, and the genes that span them, are therefore part of a protective response mechanism to oxidative stress and likely contributors to the differences seen in aerobic glycolysis (Warburg effect) in cancer cells.
常见的染色体脆性位点 FRA3B 和 FRA16D 是癌症中 DNA 不稳定性的常见位点，但它们对癌细胞生物学的贡献尚不清楚。跨越这些位点的基因（分别为 FHIT 和 WWOX）在癌细胞中经常受到干扰（增加或减少），并且两者都能够抑制肿瘤生长。虽然 WWOX 具有一些肿瘤抑制特性，但它的正常作用和对癌症的功能贡献尚未完全确定。我们发现，通过蛋白质组学和微阵列分析鉴定的果蝇 Wwox 相互作用蛋白的很大一部分在有氧代谢中具有作用。通过遗传相互作用证实了 Wwox 与 CG6439/异柠檬酸脱氢酶 (Idh) 或 Cu-Zn 超氧化物歧化酶 (Sod) 之间的功能关系。此外，Wwox 水平的改变导致内源性活性氧水平的改变。Wwox（与 FHIT 一样）有助于涉及有氧代谢和氧化应激的途径，为 WWOX 的“非经典肿瘤抑制因子”行为提供了解释。因此，脆性位点及其跨越它们的基因是氧化应激保护反应机制的一部分，可能是癌细胞中有氧糖酵解（Warburg 效应）差异的原因之一。
