Co-expression analysis of transcriptomic data from cancer and healthy specimens reveals rewiring of proteasome genes and an interaction with the XPO1 gene across several tumour types

Abstract

Abstract Background The 26S proteasome is a large intracellular multiprotein complex, that plays a homeostatic role by degrading proteins that have been tagged by ubiquitin. It is composed of 64 subunits assembled according to a well-defined structure and stoichiometry. Several proteasome subunits have been found to be overexpressed in tumours. However, comprehensive data are lacking on the relative abundance of each subunit and the impact on proteasome composition or stoichiometry. In cancer treatment, proteasome inhibitors and inhibitors of XPO1 (Exportin-1) have unexpectedly a similar range of activity, but the interaction between the two pathways has not been studied. Methods We performed gene co-expression analysis of 38 genes encoding proteasome subunits and 38 genes encoding proteins involved in nucleocytoplasmic transport in specimens from the Cancer Genome Atlas (33 tumour types) and from the Gene Tissue Expression database (32 healthy tissue types). We obtained 65 matrices, each containing Pearson correlation factors for 2964 gene pairs. We applied cluster analysis to the correlation matrices and compared the distribution of Pearson correlation coefficients of thirteen tumour types with their healthy tissue counterpart. Results Strong positive correlation (R Pearson correlation > 0.8) was observed for pairs of proteasome genes in the majority of healthy tissues, whereas the correlation for co-expression was significantly lower (R ≤ 0.50) for most gene pairs in the majority of cancer types. Cluster analysis based on gene co-expression allowed to distinguish cancers from healthy tissues in a clear-cut manner, and to identify the genes that contributed most to the separation. The crossed analysis between proteasome and nucleocytoplasmic transport genes showed that the expression of XPO1 and a subset of proteasome genes, including in particular PSMD14, is correlated in several cancer types and not in their healthy counterpart. Conclusions This analysis reveals that in cancer the co-expression of proteasome genes is significantly altered, highlighting the genes that are more often deregulated. In addition, it finds that XPO1 expression is often correlated with the expression of proteasome genes. From a therapeutic perspective, these findings support the investigation of novel targets within the proteasome and strategies of co-targeting of the proteasome and nucleocytoplasmic transport.

Keywords

• 26S proteasome
• Nucleocytoplasmic transport
• Gene co-expression
• The cancer genome atlas
• Gene tissue expression database
• XPO1