Multiproteomic 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/β-catenin,
the key nuclear effector of canonical Wnt signaling, lead to the accumulation
and stabilization of β-catenin protein with diverse effects
in cancer cells. Although the transcriptional response to Wnt/β-catenin
signaling activation has been widely studied, an integrated understanding
of the effects of oncogenic β-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 β-catenin. We generate an integrated
molecular network and use it to identify novel protein modules that
are associated with mutant or wild-type β-catenin. We identify
a DNA methyltransferase I associated subnetwork that is enriched in
cells with mutant β-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
β-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
β-catenin signaling.