Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells
Open Access
- 1 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 39 (19), 3893-3909
- https://doi.org/10.1038/s41388-020-1259-7
Abstract
The transcription factor TCF7L2 is indispensable for intestinal tissue homeostasis where it transmits mitogenic Wnt/beta-Catenin signals in stem and progenitor cells, from which intestinal tumors arise. Yet, TCF7L2 belongs to the most frequently mutated genes in colorectal cancer (CRC), and tumor-suppressive functions of TCF7L2 were proposed. This apparent paradox warrants to clarify the role of TCF7L2 in colorectal carcinogenesis. Here, we investigated TCF7L2 dependence/independence of CRC cells and the cellular and molecular consequences of TCF7L2 loss-of-function. By genome editing we achieved complete TCF7L2 inactivation in several CRC cell lines without loss of viability, showing that CRC cells have widely lost the strict requirement for TCF7L2. TCF7L2 deficiency impaired G1/S progression, reminiscent of the physiological role of TCF7L2. In addition, TCF7L2-negative cells exhibited morphological changes, enhanced migration, invasion, and collagen adhesion, albeit the severity of the phenotypic alterations manifested in a cell-line-specific fashion. To provide a molecular framework for the observed cellular changes, we performed global transcriptome profiling and identified gene-regulatory networks in which TCF7L2 positively regulates the proto-oncogene MYC, while repressing the cell cycle inhibitors CDKN2C/CDKN2D. Consistent with its function in curbing cell motility and invasion, TCF7L2 directly suppresses the pro-metastatic transcription factor RUNX2 and impinges on the expression of cell adhesion molecules. Altogether, we conclude that the proliferation-stimulating activity of TCF7L2 persists in CRC cells. In addition, TCF7L2 acts as invasion suppressor. Despite its negative impact on cell cycle progression, TCF7L2 loss-of-function may thereby increase malignancy, which could explain why TCF7L2 is mutated in a sizeable fraction of colorectal tumors.Funding Information
- Deutsche Forschungsgemeinschaft (CRC-850 B5, HE2004/11-1, 322977937/GRK2344 B03, CRC-850 C11, CRC-850 Z1)
- Carl-Zeiss-Stiftung (Az. 0563-2.8/685/4)
- Bundesministerium für Bildung und Forschung (FKZ 01ZX1708F)
This publication has 80 references indexed in Scilit:
- A colorectal cancer classification system that associates cellular phenotype and responses to therapyNature Medicine, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Comprehensive molecular characterization of human colon and rectal cancerNature, 2012
- A Critical Role for the Wnt Effector Tcf4 in Adult Intestinal Homeostatic Self-RenewalMolecular and Cellular Biology, 2012
- T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesisProceedings of the National Academy of Sciences of the United States of America, 2011
- Loss of WNT‐TCF addiction and enhancement of HH‐GLI1 signalling define the metastatic transition of human colon carcinomasEMBO Molecular Medicine, 2010
- Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancerProceedings of the National Academy of Sciences of the United States of America, 2009
- A Genome-Wide Screen for β-Catenin Binding Sites Identifies a Downstream Enhancer Element That Controls c-Myc Gene ExpressionMolecular and Cellular Biology, 2008
- A genome-wide RNAi screen for Wnt/β-catenin pathway components identifies unexpected roles for TCF transcription factors in cancerProceedings of the National Academy of Sciences of the United States of America, 2008
- The Consensus Coding Sequences of Human Breast and Colorectal CancersScience, 2006