Wnt Effector TCF4 Is Dispensable for Wnt Signaling in Human Cancer Cells

Abstract

T-cell factor 4 (TCF4), together with β-catenin coactivator, functions as the major transcriptional mediator of the canonical wingless/integrated (Wnt) signaling pathway in the intestinal epithelium. The pathway activity is essential for both intestinal homeostasis and tumorigenesis. To date, several mouse models and cellular systems have been used to analyze TCF4 function. However, some findings were conflicting, especially those that were related to the defects observed in the mouse gastrointestinal tract after Tcf4 gene deletion, or to a potential tumor suppressive role of the gene in intestinal cancer cells or tumors. Here, we present the results obtained using a newly generated conditional Tcf4 allele that allows inactivation of all potential Tcf4 isoforms in the mouse tissue or small intestinal and colon organoids. We also employed the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system to disrupt the TCF4 gene in human cells. We showed that in adult mice, epithelial expression of Tcf4 is indispensable for cell proliferation and tumor initiation. However, in human cells, the TCF4 role is redundant with the related T-cell factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1) transcription factors.

Integrative Bioinformatics Approaches to Map Potential Novel Genes and Pathways Involved in Ovarian Cancer

“…In contrast, frizzled family proteins (FZD2, FZD6, and FZD8) are directly involved in the Wnt signaling pathways because they are receptors of Wnt proteins (Janda et al, 2012). The TCF4 and RUNX2 genes are involved directly or indirectly in the Wnt signaling network, resulting in tumorigenesis (Gaur et al, 2005;Hrckulak et al, 2018;Komori, 2019). Taken together, these findings showed that node genes involved in the development of OC could be significant factors in cell cycle regulation and the Wnt signaling pathway.…”

Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells

“…Particularly relevant for colorectal carcinogenesis are the stimulation of cell proliferation and the maintenance of intestinal stem cells [6] from which colorectal tumors appear to arise [7]. In the healthy gut, these Wnt/β-Catenin pathway functions are executed exclusively via TCF7L2 [8][9][10][11]. Accordingly, inactivation of the Tcf7l2 gene in mouse models and intestinal organoids is lethal due to diminished mitogenic activity and depletion of stem and progenitor cells [8][9][10][11].…”

Nrf1 is endowed with a dominant tumor-repressing effect onto the Wnt/β-Catenin-dependent and -independent signaling networks in the human liver cancer

“…Such seemingly-confusing result appears to be coincident with the previously 'surprising' finding by Shulewitz et al [54]. Thereby, it is postulated that though TCF4 was bona fide down-expressed in Nrf1-silenced cells, the LEF/TCF family factors are also functionally redundant in the human Wnt/-catenin signaling activation stimulated by deficiency of Nrf1, as identified by Hrckulak et al [65] that TCF4 is dispensable for the Wnt signaling in human cancer cells. Notably, there exist 671 DEGs identified by transcriptomic sequencing in Nrf1-silenced cells (Table S5), of which 77 genes are implicated in the Wnt/-catenin signaling and relevant responsive effects on target gene transcription, cell division cycle, cell proliferation, and differential fates, as well as cell polarity, cell adhesion and cytoskeleton (Table S2).…”