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TCF/LEF dependent and independent transcriptional regulation of Wnt/?-catenin target genes.

ABSTRACT: During canonical Wnt signalling, the activity of nuclear ?-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of ?-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that ?-catenin occupied specific genomic regions in the absence of TCF/LEF Finally, we revealed the existence of a transcriptional activity of ?-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as ?-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of ?-catenin that bypasses the TCF/LEF transcription factors.

SUBMITTER: Doumpas N

PROVIDER: S-EPMC6331726 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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TCF/LEF dependent and independent transcriptional regulation of Wnt/β-catenin target genes.

Doumpas Nikolaos N Lampart Franziska F Robinson Mark D MD Lentini Antonio A Nestor Colm E CE Cantù Claudio C Basler Konrad K

The EMBO journal 20181113 2

During canonical Wnt signalling, the activity of nuclear β-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of β-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a gen ...[more]

PMID: 30425074

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Project description:Early in cancer development, tumour cells express vascular endothelial growth factor (VEGF), a secreted molecule that is important in all stages of angiogenesis, an essential process that provides nutrients and oxygen to the nascent tumor and thereby enhances tumor-cell survival and facilitates growth. Survivin, another protein involved in angiogenesis, is strongly expressed in most human cancers, where it promotes tumor survival by reducing apoptosis as well as favoring endothelial cell proliferation and migration. The mechanisms by which cancer cells induce VEGF expression and angiogenesis upon survivin up-regulation remain to be fully established. Since the PI3K/Akt signalling and ?-catenin-Tcf/Lef dependent transcription have been implicated in the expression of many cancer-related genes, including survivin and VEGF, we evaluated whether survivin may favor VEGF expression, release from tumor cells and induction of angiogenesis in a PI3K/Akt-?-catenin-Tcf/Lef-dependent manner. Here, we provide evidence linking survivin expression in tumor cells to increased ?-catenin protein levels, ?-catenin-Tcf/Lef transcriptional activity and expression of several target genes of this pathway, including survivin and VEGF, which accumulates in the culture medium. Alternatively, survivin downregulation reduced ?-catenin protein levels and ?-catenin-Tcf/Lef transcriptional activity. Also, using inhibitors of PI3K and the expression of dominant negative Akt, we show that survivin acts upstream in an amplification loop to promote VEGF expression. Moreover, survivin knock-down in B16F10 murine melanoma cells diminished the number of blood vessels and reduced VEGF expression in tumors formed in C57BL/6 mice. Finally, in the chick chorioallantoid membrane assay, survivin expression in tumor cells enhanced VEGF liberation and blood vessel formation. Importantly, the presence of neutralizing anti-VEGF antibodies precluded survivin-enhanced angiogenesis in this assay. These findings provide evidence for the existance of a posititve feedback loop connecting survivin expression in tumor cells to PI3K/Akt enhanced ?-catenin-Tcf/Lef-dependent transcription followed by secretion of VEGF and angiogenesis.

Dataset Information

TCF/LEF dependent and independent transcriptional regulation of Wnt/?-catenin target genes.

Publications

TCF/LEF dependent and independent transcriptional regulation of Wnt/β-catenin target genes.

Similar Datasets

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