YTHDF1 Amplifies Wnt/β-Catenin Signaling to Promote Intestinal Stemness
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ABSTRACT:
PROVIDER: PRJNA563001 | ENA |
REPOSITORIES: ENA
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Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.
2019-08-31 | GSE136664 | GEO
Project description: Not available
| S-SCDT-EMBOR-2019-49229-T | biostudies-other
Project description: Not available
| S-EPMC7132202 | biostudies-literature
Project description:N6-methyladenosine (m6A) RNA modification is the most common and conserved epigenetic modification in mRNA and has been shown to play important roles in cancer biology. As the m6A reader YTHDF1 has been reported to promote progression of hepatocellular carcinoma (HCC), it represents a potential therapeutic target. In this study, we evaluated the clinical significance of YTHDF1 using human HCC samples and found that YTHDF1 was significantly upregulated in HCCs with high stemness scores and was positively associated with recurrence and poor prognosis. Analysis of hepatoma spheroids revealed that YTHDF1 was highly expressed in liver cancer stem cells (CSCs). Stem cell-specific conditional Ythdf1 knock-in (CKI) mice treated with diethylnitrosamine showed elevated tumor burden compared with wild type mice. YTHDF1 promoted CSC renewal and resistance to the multiple tyrosine kinase inhibitors lenvatinib and sorafenib in patient-derived organoids and HCC cell lines, which could be abolished by catalytically inactive mutant YTHDF1. RNA immunoprecipitation sequencing, m6A methylated RNA immunoprecipitation sequencing, ribosome profiling, and RNA sequencing identified NOTCH1 as a direct downstream of YTHDF1. YTHDF1 bound to m6A modified NOTCH1 mRNA to enhance its stability and translation, which led to increased NOTCH1 target genes expression. NOTCH1 overexpression rescued HCC stemness in YTHDF1 deficient cells in vitro and in vivo. Lipid nanoparticles targeting YTHDF1 significantly enhanced the efficacy of lenvatinib and sorafenib in HCC in vivo. Taken together, YTHDF1 drives HCC stemness and drug resistance through a YTHDF1-m6A-NOTCH1 epitranscriptomic axis, and YTHDF1 is a potential therapeutic target for treating HCC.
2024-01-11 | GSE252752 | GEO
Project description:Abberant expression and protein localization of ESM1 were found in prostate cancer. The high expression of ESM1 is associated with prostate cancer stemness and progression. Thus, ESM1 is clinically relevant to poor overall survival and metastasis. However, the molecular mechanisms by which ESM1 contribute to prostate cancer is not yet understood. To discover the role of ESM1 mislocalization in prostate cancer, RNA-seq analysis was performed on 22Rv1 cells overexpressing with different ESM1. Our study demonstrate that nuclear ESM1 may support prostate cancer stemness by interacting with the ARM domain of β-catenin to stabilize β-catenin-Tcf4 complex and facilitate the transactivation of Wnt/β-catenin signaling targets. Our results establish the significance of ESM1 in driving metastasis in prostate cancer by coordinating the Wnt/β-catenin pathway, with implication for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in prostate cancer.
2020-12-06 | GSE157496 | GEO
Project description:Wnt signals control three functions of intestinal crypts: maintenance of Lgr5 stem cells, proliferation of transit-amplifying daughters and formation of Paneth cells. Here, we study how the Wnt effector β-catenin/Tcf4 cooperates with the Wnt-activated transcription factor Ascl2 to control a stem cell transcription program. DNA elements that are co-occupied and synergistically regulated by Ascl2 and Tcf4 specifically map to stem cell genes. In vitro, Tcf4-/- mini-guts are rescued by Ascl2 expression, while Ascl2-/- organoids are rescued by Wnt signaling. A direct auto-activatory loop leads to an on/off expression pattern of Ascl2 with a threshold that depends on the previous state. Wnt/R-spondin1 activates this loop. This mechanism interprets Wnt levels in crypts and translates this continuous signal into a discrete Ascl2 âonâ or âoffâ decision. In turn Ascl2, together with β-catenin/Tcf, activates stem cell genes. Thus, Ascl2 forms a transcriptional 'stemness switch' that is both Wnt-responsive and Wnt-dependent Examination of Tcf4, B-catenin and Ascl2 DNA occupancy in murine intestinal organoids and human colorectal cancer cell lines *** Original raw files unavailable due to loss during backup ***
2016-07-15 | E-GEOD-84456 | biostudies-arrayexpress
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
Project description:The contribution of deubiquitylating enzymes to b-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as APC-truncation- specific regulator enhancer of b-Catenin stability, potentiating WNT signalling pathway in CRC and cancer stem cells. Mechanistically, interaction studies in various CRC cell lines and in vitro binding studies, together with computational modelling, revealed that USP10 binding to b-Catenin is mediated via its USP10 unstructured N-terminus and requires truncated in the absence of full-length APC. Notably, loss of USP10 in CRISPR engineered intestinal organoids reduces tumorigenic properties of CRC cells and organoids, and blocks the super competitor-properties of APC-mutated intestinal cells, elicits induces the expression of differentiation genes, and opposes the APC-truncated phenotype in an intestinal hyperplasia model of D.melanogaster. Taken together, our findings reveal USP10s role in intestinal tumourigenesis by stabilising b-Catenin, leading to aberrant WNT signalling, enhancing cancer cell stemness and implicate the DUB USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.
2024-01-01 | GSE226364 | GEO
Project description:Background and Purpose: Our previous work reported that galaxamide, a cyclopeptide extracted from the seaweed Galaxaura filamentosa, showed antiproliferative activity against HeLa cells by MTT assay. However, the therapeutic effects in vivo and potential mechanisms to eliminate cervical cancer cells remain unknown. Experimental Approach: HeLa cells were obtained as a cervical carcinoma in vitro model. The growth-inhibitory effects of galaxamide in HeLa cells and xenograft mouse models were investigated. RNA-seq was employed to analyse the main target of galaxamide in HeLa cells. Immunostaining, qRT‒PCR and Western blotting were applied to test the pharmacological effects in vitro and in vivo. Key Results: Galaxamide significantly inhibited cell growth, colony formation, migration, and invasion and induced cell apoptosis by inhibiting the Wnt signalling pathway in HeLa cells. RNA sequencing revealed that galaxamide regulated stemness via the Wnt6 signalling pathway in HeLa cells. By analysing The Cancer Genome Atlas database (TCGA), Wnt6 was found to be negatively/positively correlated with stemness- and apoptosis-related genes in human cervical cancer. Cancer stem-like cells (CSCs) isolated and enriched from HeLa cells demonstrated elevated Wnt6 and β-catenin genes compared with nonstem HeLa cells. After galaxamide treatment, CSCs showed abrogation of sphere-forming ability, along with inhibition of stemness-related and Wnt pathway genes. Galaxamide treatment was accompanied by the induction of apoptosis in HeLa cells, which was consistent with the results in BALB/c nude mice. Conclusion and Implications: Our results provide preclinical evidence that suppression of stemness by downregulating the Wnt signalling pathway is the molecular mechanism by which galaxamide effectively inhibits cell growth and induces apoptosis in cervical cancer cells.
2023-04-03 | GSE228509 | GEO
Project description:Breast cancer is one of the most common types of cancer in women. One key signaling pathway known to regulate tumor growth, metabolic adaptation, and cellular stress response in breast cancer is Wnt signaling. Breast cancer patients, specifically triple negative breast cancer (TNBC), with upregulated Wnt signaling often have a poor clinical prognosis. However, the effects of Wnt/β-catenin signaling on the nucleolus and the resultant impact on cancer development and progression remain unclear. A notable reduction was observed in the number of nucleoli per nucleus in response to Wnt/β-catenin signaling inhibition in multiple TNBC cell lines. Our comparative proteomic analysis revealed several changes in the composition of the nucleolar proteome of TNBC cells upon inhibition of Wnt signaling. Overall, we demonstrate that Wnt/β-catenin signaling will affects nucleolar functionality and thus influences breast cancer progression. Understanding the role of Wnt signaling in the nucleolus and breast cancer is a critical step towards developing novel therapeutic options for the treatment of breast cancer.
2021-03-05 | PXD021181 | Pride