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The oncogene FOXQ1 is a selective activator of Wnt/β-catenin signalling

ABSTRACT: The forkhead box transcription factor FOXQ1 is aberrantly induced in various cancers, and contributes to tumour growth and metastasis. It has been suggested that the oncogenic potential of FOXQ1 may be explained by its activation of the Wnt/β-catenin signalling pathway.However, the mode of action of FOXQ1 in the Wnt pathway remains to be resolved. Here we report that FOXQ1 is bimodal transcriptional activator of Wnt target gene expression in normal and cancer cells. Using co-immunoprecipitation, proximity proteomics, and reporter assays, we show that FOXQ1 engages the Wnt transcriptional complex to promote gene expressionvia TCF/LEF transcription factors.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Lavanya Moparthi

LAB HEAD: Stefan Koch

PROVIDER: PXD030464 | Pride | 2022-10-05

REPOSITORIES: Pride

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The oncogenic transcription factor FOXQ1 is a differential regulator of Wnt target genes.

Pizzolato Giulia G Moparthi Lavanya L Söderholm Simon S Cantù Claudio C Koch Stefan S

Journal of cell science 20221010 19

The forkhead box transcription factor FOXQ1 contributes to the pathogenesis of carcinomas. In colorectal cancers, FOXQ1 promotes tumour metastasis by inducing epithelial-to-mesenchymal transition (EMT) of cancer cells. FOXQ1 may exacerbate cancer by activating the oncogenic Wnt/β-catenin signalling pathway. However, the role of FOXQ1 in the Wnt pathway remains to be resolved. Here, we report that FOXQ1 is an activator of Wnt-induced transcription and regulator of β-catenin target gene expression ...[more]

PMID: 36124643

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The oncogenic transcription factor FOXQ1 is a bimodal regulator of Wnt target genes

Project description:The forkhead box transcription factor FOXQ1 is aberrantly induced in various cancers, and contributes to tumour growth and metastasis. It has been suggested that the oncogenic potential of FOXQ1 may be explained by its activation of the Wnt/β-catenin signalling pathway. However, the mode of action of FOXQ1 in the Wnt pathway remains to be resolved. Here we report that FOXQ1 is bimodal transcriptional regulator of Wnt target gene expression in normal and cancer cells. Using co-immunoprecipitation, proximity proteomics, and reporter assays, we show that FOXQ1 partly engages the Wnt transcriptional complex to promote gene expression via TCF/LEF transcription factors.

2022-10-05 | PXD035624 | Pride

FOX transcription factors are common regulators of Wnt/β-catenin signaling

Project description:The Wnt/β-catenin signaling pathway is a critical regulator of development and stem cell maintenance. Mounting evidence suggests that the context-specific outcome of Wnt signaling is determined by the collaborative action of multiple transcription factors, including members of the highly conserved forkhead box (FOX) protein family. The contribution of FOX transcription factors to Wnt signaling has not been investigated in a systemic manner. Here, by combining β-catenin reporter assays with Wnt pathway-focused qPCR arrays and proximity proteomics of selected FOX family members, we determine that most FOX proteins are involved in the regulation of Wnt pathway activity and the expression of Wnt ligands and target genes. We conclude that FOX proteins are common regulators of the Wnt/β-catenin pathway that may control the outcome of Wnt signaling in a tissue-specific manner.

2023-04-19 | PXD038811 | Pride

Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer

Project description:The Wnt signaling pathway is playing a crucial role during development and adult tissue homeostasis. However, the tissue and cell type-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Proximity-dependent biotinylation assay (BioID) coupled with mass spectrometry identified transcriptional co-regulators required for FOXB2-dependent Wnt activation.

2019-10-16 | PXD015725 | Pride

Frizzled receptors facilitate Tiki inhibition of Wnt signaling at the cell surface

Project description:Tiki antagonizes Wnt3a signaling by cleaving and inactivating Wnt3a in Wnt-producing cells. Tiki also functions in Wnt-receiving cells to antagonize Wnt signaling by an unknown mechanism. Here, we demonstrate that Tiki inhibition of Wnt signaling at the cell surface requires Frizzled receptors. Tiki associates with the Wnt-FZD complex and cleaves the N-terminus of Wnt3a or Wnt5a, preventing the Wnt-FZD complex from recruiting and activating the coreceptor LRP6 or ROR1/2 without affecting Wnt-FZD complex stability. Intriguingly, we demonstrate that the N-terminus of Wnt3a is required for Wnt3a binding to LRP6 and activating β-catenin signaling, while the N-terminus of Wnt5a is dispensable for recruiting and phosphorylating ROR1/2. Both Tiki enzymatic activity and its association with the Wnt-FZD complex contribute to its inhibitory function on Wnt5a. Our study uncovers the mechanism by which Tiki antagonizes Wnt signaling at the cell surface and reveals a negative role of FZDs in Wnt signaling by acting as Tiki cofactors. Our findings also reveal an unexpected role of the Wnt3a N-terminus in the engagement of the coreceptor LRP6.

2023-05-24 | PXD040942 | Pride

A whole genome CRISPR screen identifies AHR loss as a mechanism of resistance to a PARP7 inhibitor

Project description:Inhibitors directed towards PARP1 and PARP2 are approved agents for the treatment of BRCA-related cancers. Other members of the PARP family have also been implicated in cancer and are being assessed as therapeutic targets in cancer and other diseases. In fact, an inhibitor of PARP7 (RBN-2397) has now reached early-stage human clinical trials. Here, we performed a genome-wide CRISPR screen for genes that modify the response of cells to RBN-2397. We identify the polycyclic aromatic hydrocarbon receptor AHR and multiple components of the cohesin complex as determinants of resistance to this agent. Activators and inhibitors of AHR modulate the cellular response to PARP7 inhibition, suggesting potential combination therapy approaches.

2022-04-06 | PXD028733 | Pride

RNA-BioID of lncRNA HOTAIR in Flp-In T-REx cells

Project description:Accumulating evidence highlights the role of long non-coding RNAs (lncRNA) in cellular homeostasis, and their dysregulation in disease settings. Most lncRNAs function by interacting with proteins or protein complexes. While several orthogonal methods have been developed to identify these proteins, each method has its inherent strengths and limitations. Here, we combine two RNA-centric methods ChIRP-MS and RNA-BioID to obtain a comprehensive list of proteins that interact with the well-known lncRNA HOTAIR. Overexpression of HOTAIR has been associated with a metastasis-promoting phenotype in various cancers. Although HOTAIR is known to bind with PRC2 and LSD1 protein complexes, an unbiased and comprehensive method to map its interactome has not yet been performed. Both ChIRP-MS and RNA-BioID data sets show an association of HOTAIR with mitoribosomes, suggesting HOTAIR has functions independent of its (post-)transcriptional mode-of-action.

2022-02-15 | PXD029058 | Pride

Analysis of RNA polymerase II interacting proteins in wild-type and spt6-1004 yeast cells.

Project description:The histone chaperone Spt6 is involved in promoting elongation of RNA polymerase II (RNAPII), maintaining chromatin structure, regulating co-transcriptional histone modifications, and controlling mRNA processing. These diverse functions of Spt6 are partly mediated through its interactions with RNAPII and other factors in the transcription elongation complex. In this study, we used mass spectrometry to characterize the differences in RNAPII interacting factors between wild-type cells and those depleted for Spt6, leading to the identification of proteins that depend on Spt6 for their interaction with RNAPII. In all, eight samples were processed - four genotypes (1. SPT6, RPB3-untagged; 2. SPT6, RPB3-tagged; 3. spt6-1004, RPB3-untagged; 4. spt6-1004; RPB3-tagged) in biological duplicates.

2021-12-05 | PXD027708 | Pride

circRIG-I associated proteins in HEK293T

Project description:We use Proximity biotinylation to find circRIG-I associated proteins in HEK293T.

2022-11-16 | PXD037928 | Pride

KSHV ORF18 TurboID in human iSLK cell lines

Project description:Beta- and gamma-herpesviruses transcribe their late genes in a manner distinct from host transcription. This process is directed by a complex of viral transcriptional activator proteins that hijack cellular RNA polymerase II, and an unknown set of additional factors. We employed proximity labeling to identify the ensemble of viral and cellular proteins dynamically associated with the KSHV late gene transcriptional complex late during infection.

2023-04-06 | PXD039694 | Pride

A degradation motif in STAU1 defines a novel family of proteins involved in inflammation

Project description:Cancer development is regulated by inflammation. Staufen 1 (STAU1) is an RNA-binding protein whose expression level is critical in cancer cells as it is related to cell proliferation or cell death. STAU1 expression levels are downregulated during mitosis due to its degradation by the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). In this paper, we map the molecular determinant involved in STAU1 degradation in mitosis to amino acids 38-50 and, by alanine scanning, we shorten the motif to F39PxPxxLxxxxL50 (FPL-motif). Mutation of the FPL-motif prevents STAU1 degradation by APC/C. Interestingly, a search in databases reveals that the FPL-motif is shared by 15 additional proteins most of them being involved in inflammation. We show that one of these proteins, MAP4K1, is indeed degraded via the FPL-motif; however, it is not a target of APC/C. Using proximity labeling with STAU1, we identify TRIM25, an E3-ubiquitin ligase involved in the innate immune response and interferon production, as responsible for STAU1 and MAP4K1 degradation, dependent on the FPL-motif. These results are consistent with previous studies that linked STAU1 to cancer-induced inflammation and identify a novel degradation motif that likely coordinates a novel family of proteins involved in inflammation.

2023-03-11 | PXD036675 | Pride

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