Regulation of protein complex partners as a compensatory mechanism in aneuploid tumors

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.

Automated summary

Aneuploidy plays an important role in cancer, affecting the proteome and leading to expression changes not only in aneuploid chromosomes but also in non-aneuploid ones. Proteins from aneuploid chromosomes tend to co-enrich with each other, and the complexes of the cellular core machinery are under functional selection to maintain stoichiometric balance. The success of a tumor in dealing with aneuploidy-induced stoichiometric imbalance impacts cellular protein degradation programs and patient survival.