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M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189880 | GEO | 2024/11/30

REPOSITORIES: GEO

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M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression [RNA-seq]

Project description:Despite advances in clinical diagnosis and treatment, the prognosis of patients with osteosarcoma (OS) remains poor, and the treatment efficacy has plateaued. Therefore, it is important to identify new therapeutic targets for OS. N6-methyladenosine (m6A) modification has been reported to participate in tumor malignancy. In this study, functional screening found that the m6A demethylase FTO could be a candidate therapeutic target for OS. Upregulated FTO in OS could predict a poorer prognosis. FTO promoted the growth and metastasis of OS in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed to identify DACT1 as a potential target of FTO. In vitro assays demonstrated that FTO could reduce the mRNA stability of DACT1 via m6A demethylation, which decreased DACT1 expression and further activated the Wnt signaling pathway. The oncogenic effect of FTO on OS was dependent on DACT1. In addition, the m6A reader IGF2BP1 was validated to participate in the regulation of DACT1. Entacapone, a conventional drug for Parkinson's disease, was confirmed to suppress OS via m6A-mediated regulation through the FTO/DACT1 axis. Our findings demonstrate that FTO may be a novel therapeutic target and that entacapone has the preclinical value to be repurposed for OS.

2024-11-30 | GSE189878 | GEO

M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression [MeRIP-seq]

2024-11-30 | GSE189877 | GEO

M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression

Project description:M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression

| PRJNA784938 | ENA

M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression [RNA-seq]

Project description:M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression [RNA-seq]

| PRJNA784947 | ENA

M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression [MeRIP-seq]

Project description:M6A Demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression [MeRIP-seq]

| PRJNA784948 | ENA

m6A demethylase FTO promotes tumor progression via regulation of lipid metabolism in esophageal cancer.

Project description:BackgroundEpitranscriptomics studies have contributed greatly to the development of research on human cancers. In recent years, N6-methyladenosine (m6A), an RNA modification on the N-6 position of adenosine, has been found to play a potential role in epigenetic regulation. Therefore, we aimed to evaluate the regulation of cancer progression properties by m6A.ResultsWe found that m6A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in esophageal cancer (EC) stem-like cells, and that its level was also substantially increased in EC tissues, which was closely correlated with a poor prognosis in EC patients. FTO knockdown significantly inhibited the proliferation, invasion, stemness, and tumorigenicity of EC cells, whereas FTO overexpression promoted these characteristics. Furthermore, integrated transcriptome and meRIP-seq analyses revealed that HSD17B11 may be a target gene regulated by FTO. Moreover, FTO promoted the formation of lipid droplets in EC cells by enhancing HSD17B11 expression. Furthermore, depleting YTHDF1 increased the protein level of HSD17B11.ConclusionsThese data indicate that FTO may rely on the reading protein YTHDF1 to affect the translation pathway of the HSD17B11 gene to regulate the formation of lipid droplets in EC cells, thereby promoting the development of EC. The understanding of the role of epitranscriptomics in the development of EC will lay a theoretical foundation for seeking new anticancer therapies.

| S-EPMC9107638 | biostudies-literature

m6A demethylase FTO suppresses pancreatic cancer tumorigenesis by demethylating <i>PJA2</i> and inhibiting Wnt signaling.

Project description:Pancreatic cancer is the deadliest malignancy of the digestive system and is the seventh most common cause of cancer-related deaths worldwide. The incidence and mortality of pancreatic cancer continue to increase, and its 5-year survival rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most abundant reversible RNA modification in various eukaryotic messenger and long noncoding RNAs and plays crucial roles in the occurrence and development of cancers. However, the role of m6A in pancreatic cancer remains unclear. The present study aimed to explore the role of m6A and its regulators in pancreatic cancer and assess its underlying molecular mechanism associated with pancreatic cancer cell proliferation, invasion, and metastasis. Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. Altogether, this study describes new, potential molecular therapeutic targets for pancreatic cancer that could pave the way to improve patient outcome.

| S-EPMC8385122 | biostudies-literature

Downregulation of the FTO m<sup>6</sup>A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors.

Project description:Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N6-methyladenosine (m6A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m6A and altered 3'-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.

| S-EPMC10734094 | biostudies-literature

N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability.

Project description:The fat mass and obesity-associated protein (FTO) is an N6-Methyladenosine (m6A) demethylase, which has been revealed to play critical roles in tumorigenesis. However, its role in the development and progression of prostate cancer (PCa) remains poorly understood. Here, we aimed to investigate the function and clinical relevance of FTO in PCa. Our results demonstrated that FTO was notably downregulated in PCa tissues compared with the paired normal tissues. In addition, the decreased expression of FTO was correlated with poor prognosis of PCa. Functional experiments showed that depletion of FTO promoted the proliferation and metastasis of PCa both in vitro and in vivo. Conversely, ectopic expression of FTO exhibited the opposite effects. Combined with RNA-sequencing, MeRIP-RT-qPCR, and mRNA stability assays indicated chloride intracellular channel 4(CLIC4) was a functional target of FTO-mediated m6A modification. FTO depletion significantly increased the m6A level of CLIC4 mRNA and then reduced the mRNA stability. In conclusion, our findings suggest that FTO suppresses PCa proliferation and metastasis through reducing the degradation of CLIC4 mRNA in an m6A dependent manner. FTO may be used as a promising novel therapeutic target and prognostic evaluation biomarker for PCa.

| S-EPMC8994758 | biostudies-literature

m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation.

Project description:N6-methyladenosine (m6A) acts as the most common mRNA modification in mammal cells. Fat Mass and Obesity-associated protein (FTO) is the firstly identified demethylase in the m6A modification. This research tries to discover the potential roles of FTO in the m6A modification in the hepatocellular carcinoma (HCC). FTO level was found to be up-regulated in the HCC tissue and cells. The over-expression of FTO was correlated to the poor prognosis of HCC individuals. Knockdown of FTO suppressed the proliferation and in vivo tumor growth, and induced the G0/G1 phase arrest. Mechanically, FTO triggered the demethylation of PKM2 mRNA and accelerated the translated production. Overall, this finding suggests the critical function of FTO in the HCC oncogenesis and its m6A modification.

| S-EPMC6789218 | biostudies-literature

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