β-catenin-independent regulation of Wnt target genes by RoR2 and ATF2/ATF4 in colon cancer cells

Abstract

Wnt signaling is an evolutionarily conserved signaling route required for development and homeostasis. While canonical, β-catenin-dependent Wnt signaling is well studied and has been linked to many forms of cancer, much less is known about the role of non-canonical, β-catenin-independent Wnt signaling. Here, we aimed at identifying a β-catenin-independent Wnt target gene signature in order to understand the functional significance of non-canonical signaling in colon cancer cells. Gene expression profiling was performed after silencing of key components of Wnt signaling pathway and an iterative signature algorithm was applied to predict pathway-dependent gene signatures. Independent experiments confirmed several target genes, including PLOD2, HADH, LCOR and REEP1 as non-canonical target genes in various colon cancer cells. Moreover, non-canonical Wnt target genes are regulated via RoR2, Dvl2, ATF2 and ATF4. Furthermore, we show that the ligands Wnt5a/b are upstream regulators of the non-canonical signature and moreover regulate proliferation of cancer cells in a β-catenin-independent manner. Our experiments indicate that colon cancer cells are dependent on both β-catenin-dependent and –independent Wnt signaling routes for growth and proliferation.

Identification of microRNA-451a as a Novel Circulating Biomarker for Colorectal Cancer Diagnosis

“…The ROR2 protein is a transmembrane receptor for Wnt noncanonical pathway activation. Recent study revealed that the noncanonical Wnt target genes are dependent on ROR2 [ 46 ]. Lara et al also demonstrated that ROR2 is repressed by aberrant promoter of hypermethylation in CRC tissues [ 47 ].…”

Wnt-11 as a Potential Prognostic Biomarker and Therapeutic Target in Colorectal Cancer

“…Consistent with this, FZD7 gene silencing reduces migration of WNT11-transfected HCT116 cells [6]. However, FZD7 gene silencing also reduces Wnt-β-catenin signaling [10] and FZD 7 is also a receptor for Wnt-3A [11,12], which increases CRC cell proliferation [13], and for Wnt-2B, which drives the mesenchymal to epithelial transition (MET) [14]. Moreover, FZD 8 transduces Wnt-11 signals that promote prostate cancer cell migration, invasion and the epithelial mesenchymal transition (EMT) [15].…”

Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer

“…Deregulation of the canonical Wnt pathway has been implicated in cancers, but the roles of the non-canonical Wnt pathway in cancers remain largely unexplored. Some reports suggest the tumour-promoting [ 55 , 56 ] or repressive [ 57 ] functions of non-canonical Wnt pathway in CRC development. Voloshanenko et al proposed that WNT5A/B (the non-canonical ligands) regulate the expression of non-canonical Wnt target genes, such as PLOD2 and HADH, which are necessary for the proliferation and viability of CRC cells [ 56 ].…”

“…Some reports suggest the tumour-promoting [ 55 , 56 ] or repressive [ 57 ] functions of non-canonical Wnt pathway in CRC development. Voloshanenko et al proposed that WNT5A/B (the non-canonical ligands) regulate the expression of non-canonical Wnt target genes, such as PLOD2 and HADH, which are necessary for the proliferation and viability of CRC cells [ 56 ]. Recent work has also identified a direct role for WNT5A in promoting the migration and invasion of CRC cells [ 55 ].…”