Extensive protein dosage compensation in aneuploid human cancers

Abstract

Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we have conducted an analysis of hundreds of human cancer cell lines with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins exhibit dosage compensation and fail to change by the degree expected based on chromosome copy number alone. We uncovered a variety of gene groups that were recurrently buffered upon both chromosome gain and loss, including protein complex subunits and cell cycle genes. Several genetic and biophysical factors were predictive of protein buffering, highlighting complex post-translational regulatory mechanisms that maintain appropriate gene product dosage. Finally, we established that chromosomal aneuploidy has an unexpectedly moderate effect on the expression of oncogenes and tumor suppressors, demonstrating that these key cancer drivers can be subject to dosage compensation as well. In total, our comprehensive analysis of aneuploidy and dosage compensation across cancers will help identify the key driver genes encoded on altered chromosomes and will shed light on the overall consequences of aneuploidy during tumor development.

Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania

“…Firstly, compensated proteins were enriched for subunits of macromolecular protein complexes (15.6% versus 1.8% in the background set). This observation matches several observations in aneuploid yeast and human (including cancer) cell lines 46,47,53–56 that also detected protein complex subunits to be highly prevalent amongst compensated proteins. It can be explained by the fact that individual subunits of macromolecular complexes are typically unstable unless assembled into a stable complex 46 .…”

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

“…We expect that with an increase of protein complex measurements, this number will substantially grow. This novel compensatory mechanism complements the previously described dosage compensation addressing the differential expression of complex subunits directly on the aneuploid chromosomes 5,10 . Together they might largely prevent the otherwise detrimental overexpression of orphan complex subunits.…”

“…Structural properties of proteins have an effect on the degree of post-transcriptional buffering on changes induced by CNAs, for example proteins with larger interface size showed larger degree of buffering 9 . Recently, post-transcription regulation has been identified as a dosage compensation mechanism in response to aneuploidy in cancer cell lines 10 .…”

Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo

“…Myc activation, on the other hand, seems to be CIN-specific, as evidenced by the recurrent copy number amplifications both in our mouse cohort and across different human cancers. Strikingly, the lack of transposon insertions in Myc, combined with the lack of transcriptional upregulation of MYC in human cancers above its amplification status ( 48 ), suggests that CIN is required exactly because it enables these copy number amplifications and MYC as an oncogene is inert to epigenetic modulation. Previously, MYC-driven cancers have been described to be immune exclusionary by matter of the protein itself ( 49 ).…”