Complex-based analysis of dysregulated cellular processes in cancer

TL;DR

This paper presents a systematic analysis of protein complexes and their transcriptional regulation in cancer, revealing key complexes and TFs involved in tumor mechanisms through integrated data analysis and a novel log-linear model.

Contribution

It introduces a new integrative approach combining PPI and gene expression data with a log-linear model to identify cancer-related complexes and their regulation by TFs.

Findings

Complexes involved in genome stability and cell proliferation show significant expression changes.

Tumors exhibit both decreases and increases in complex expression, indicating compensatory mechanisms.

TFs regulate these complexes cooperatively and counteractively, influencing cancer progression.

Abstract

Background: Differential expression analysis of (individual) genes is often used to study their roles in diseases. However, diseases such as cancer are a result of the combined effect of multiple genes. Gene products such as proteins seldom act in isolation, but instead constitute stable multi-protein complexes performing dedicated functions. Therefore, complexes aggregate the effect of individual genes (proteins) and can be used to gain a better understanding of cancer mechanisms. Here, we observe that complexes show considerable changes in their expression, in turn directed by the concerted action of transcription factors (TFs), across cancer conditions. We seek to gain novel insights into cancer mechanisms through a systematic analysis of complexes and their transcriptional regulation. Results: We integrated large-scale protein-interaction (PPI) and gene-expression datasets to identify complexes that exhibit significant changes in their expression across different conditions in cancer. We devised a log-linear model to relate these changes to the differential regulation of complexes by TFs. The application of our model on two case studies involving pancreatic and familial breast tumour conditions revealed: (i) complexes in core cellular processes, especially those responsible for maintaining genome stability and cell proliferation (e.g. DNA damage repair and cell cycle) show considerable changes in expression; (ii) these changes include decrease and countering increase for different sets of complexes indicative of compensatory mechanisms coming into play in tumours; and (iii) TFs work in cooperative and counteractive ways to regulate these mechanisms. Such aberrant complexes and their regulating TFs play vital roles in the initiation and progression of cancer.