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TCF7L2 silencing results in altered gene expression patterns accompanied by local genomic reorganization

ABSTRACT: Canonical Wnt signaling is crucial for intestinal homeostasis as TCF4, the major Wnt signaling effector in the intestines, is required for stem cell maintenance. The capability of TCF4 to maintain the stem cell phenotype is contingent upon β-catenin, a potent transcriptional activator, which interacts with histone acetyltransferases and chromatin remodeling complexes. We used RNAi to explore the influence of TCF4 on chromatin structure (Hi-C) and gene expression (RNA sequencing) across a 72-hour time series in colon cancer. We found that TCF4 reduction results in a disproportionate up-regulation of gene expression, including a powerful induction of SOX2. Integration of RNA sequencing and Hi-C data revealed a TAD boundary loss, which occurred concomitantly with the over-expression of a cluster of CEACAM genes on chromosome 19. We identified EMT and E2F as the two most deregulated pathways upon TCF4 depletion and LUM, TMPO, and AURKA as highly influential genes in these networks using measures of centrality. Results from gene expression, chromatin structure, and centrality analyses were integrated to generate a list of candidate transcription factors crucial for colon cancer cell homeostasis. The top ranked factor was c-JUN, an oncoprotein known to interact with TCF4 and β-catenin, confirming the usefulness of this approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151970 | GEO | 2020/06/08

REPOSITORIES: GEO

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Project description:To analyze whether Wnt inhibitors LF3 and ICG-001 have similar influence on the gene expression of mouse salivary gland cancer stem cells Wnt/β-catenin signaling is a system that is essential for embryogenesis and tissue homeostasis which has been highly conserved through evolution. A deregulation of Wnt/β-catenin signals can initiate and promote human cancers, specifically of the colon, head and neck. As such, Wnt/β-catenin signaling represents an attractive target for cancer therapy. So far, however, no rationally developed compound targeting Wnt signaling has found clinical use. The interaction between β-catenin and TCF4 is necessary in the transduction of the signal; here we performed a High-Throughput-Screening (HTS) using AlphaScreen and ELISA techniques to identify small molecules that specifically disrupt this interaction. We identified compound LF3, a 4-thioureido-benzenesulfonamide derivative, as a robust inhibitor of β-catenin/TCF4 interactions and thus a good starting point for drug discovery, as suggested by Lipinski's “rule of five.” LF3 inhibited Wnt/β-catenin signaling in cells with exogenous reporters and in colon cancer cells with endogenously high Wnt activity. Medicinal chemistry identified an essential core structure and residues that could not be modified in LF3. Compound LF3 inhibited a number of features of cancer cells related to Wnt signaling, including high cell motility in Boyden chamber assays, hyperproliferation through induction of cell cycle arrest at the G1 phase, and the overexpression of key Wnt target genes. LF3 does not cause apoptosis or cell death or interfere with cadherin-mediated cell-cell adhesion. Remarkably, the self-renewal capacity of cancer stem cells was blocked by LF3 in concentration-dependent manners, as demonstrated by examination of sphere formation of colon and head and neck cancer stem cells in serum-free, non-attached conditions. LF3 also reduced tumor growth and induced differentiation in colon tumors in mouse xenografts. LF3 is thus a specific inhibitor of canonical Wnt signaling with a significant potential for further development for preclinical and clinical studies in cancer treatment.

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TCF7L2 silencing results in altered gene expression patterns accompanied by local genomic reorganization

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