Multi-proteomic and transcriptomic analysis of oncogenic β-catenin molecular networks.

The dysregulation of Wnt signaling is a frequent occurrence in many different cancers. Oncogenic mutations of CTNNB1/beta-catenin, the key nuclear effector of canonical Wnt signaling, lead to the accumulation and stabilization of beta-catenin protein with diverse effects in cancer cells. Although the transcriptional response to Wnt/beta-catenin signaling activation has been widely studied, an integrated understanding of the effects of oncogenic beta-catenin on molecular networks is lacking. We used affinity-purification mass spectrometry (AP-MS), label-free liquid chromatography tandem mass spectrometry, and RNA-Seq to compare protein protein interactions, protein expression, and gene expression in colorectal cancer cells expressing mutant (oncogenic) or wild-type beta-catenin. We generate an integrated molecular network and use it to identify novel protein modules that are associated with mutant or wild-type beta-catenin. We identify a DNA methyltransferase I associated subnetwork that is enriched in cells with mutant beta-catenin and a subnetwork enriched in wild-type cells associated with the CDKN2A tumor suppressor, linking these processes to the transformation of colorectal cancer cells through oncogenic beta-catenin signaling. In summary, multiomics analysis of a defined colorectal cancer cell model provides a significantly more comprehensive identification of functional molecular networks associated with oncogenic beta-catenin signaling.