Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Elife. 2022 May 16;11:e75526. doi: 10.7554/eLife.75526.
Aneuploidy, a state of chromosome imbalance, is a hallmark of human tumors, but its role in cancer still remains to be fully elucidated. To understand the consequences of whole-chromosome-level aneuploidies on the proteome, we integrated aneuploidy, transcriptomic, and proteomic data from hundreds of The Cancer Genome Atlas/Clinical Proteomic Tumor Analysis Consortium tumor samples. We found a surprisingly large number of expression changes happened on other, non-aneuploid chromosomes. Moreover, we identified an association between those changes and co-complex members of proteins from aneuploid chromosomes. This co-abundance association is tightly regulated for aggregation-prone aneuploid proteins and those involved in a smaller number of complexes. On the other hand, we observed that complexes of the cellular core machinery are under functional selection to maintain their stoichiometric balance in aneuploid tumors. Ultimately, we provide evidence that those compensatory and functional maintenance mechanisms are established through post-translational control, and that the degree of success of a tumor to deal with aneuploidy-induced stoichiometric imbalance impacts the activation of cellular protein degradation programs and patient survival.
非整倍体，即染色体不平衡的状态，是人类肿瘤的标志特征，但它在癌症中的作用仍有待充分阐明。为了了解全染色体水平非整倍体对蛋白质组的影响，我们整合了来自数百个癌症基因组图谱/临床蛋白质组肿瘤分析联盟肿瘤样本的非整倍体、转录组和蛋白质组数据。我们发现，在其他非整倍体染色体上发生了大量出人意料的表达变化。此外，我们还发现这些变化与非整倍体染色体上蛋白质的共同复合物成员之间存在关联。对于易于聚集的非整倍体蛋白和那些参与数量较少复合物的蛋白，这种共同丰度的关联受到严格的调控。另一方面，我们观察到细胞核心机器的复合物受到功能选择的限制，以维持在非整倍体肿瘤中的化学计量平衡。最终，我们提供的证据表明，这些补偿和功能维持机制是通过翻译后控制建立的，肿瘤应对非整倍体诱导的化学计量失衡的成功程度会影响细胞蛋白质降解程序的激活和患者的生存。
