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

Abstract

Dys-regulation of Wnt signalling is a frequent occurrence in many different cancers. Oncogenic mutations of CTNNB1/β-catenin, the key nuclear effector of canonical Wnt signalling, lead to 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 LC-MS/MS 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 (DNMT1) associated sub-network that is enriched in cells with mutant β-catenin and a sub-network enriched in wild-type cells associated with the CDKN2A tumor suppressor linking these processes to transformation of colorectal cancer cells through oncogenic β-catenin signaling. In summary, multi-omics analysis of a defined colorectal cancer cell model provides for a significantly more comprehensive identification of functional molecular networks associated with oncogenic β-catenin signaling.

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Identifiers

ORCID for Rob M. Ewing: orcid.org/0000-0001-6510-4001

ORCID for Paul Skipp: orcid.org/0000-0002-2995-2959

ORCID for Yihua Wang: orcid.org/0000-0001-5561-0648

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