m<sup>6</sup>A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2

Wang, Wei; He, Ying; Zhai, Limin; Chen, Long-Jiang; Yao, Lichao; Wu, Lun; Tang, Zhi‐Gang; Ning, Jinzhuo

doi:10.1080/15592294.2022.2061117

Cited by 20 publications

(7 citation statements)

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“…Fat mass and obesity-associated protein (FTO) belongs to the non-heme Fe 2+ /α-ketoglutarate-dependent dioxygenase alkB family of proteins [ 9 ]. As the first m6A demethylase identified to be dysregulated in various tumours, FTO is upregulated in pancreatic, gastric, and bladder cancers and promotes tumour growth and metastasis [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Reduced FTO expression in the liver, prostate, papillary thyroid, colorectal, and lung adenocarcinoma has been associated with poor prognosis [ 22 , 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…In pancreatic cancer cells, inhibiting FTO expression reduces cell proliferation by increasing the m6A modification of the 3′ UTR region of platelet-derived growth factor-C (PDGFC) and regulates the degradation of PDGFC at the transcriptional level in an m6A-YTHDF2 dependent manner [ 10 ]. FTO can also promote pancreatic cancer progression by reducing the stability of TFPI-2 mRNA mediated by m6A-YTHDF1 [ 11 ]. FTO knockout suppresses the expression of c-Jun, JunB, and c/EBPβ, thereby impairing glycolysis and restoring CD8+ T cell function, which inhibits tumour growth [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

Sun¹,

Zhang²,

Bi³

et al. 2022

Cancers

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Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial–mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3′ UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

Sun¹,

Zhang²,

Bi³

et al. 2022

Cancers

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“…In melanoma cells, FTO increased the RNA stability of programmed cell death 1 ligand 1 (PD-L1) by inducing m6A demethylation, and prevented PD-L1 from being recognized by YTHDF2 38 . In pancreatic cancer cells, although FTO still inhibited the m6A modification of its target tissue factor pathway inhibitor-2 (TFPI2), unlike PD-L1, the mRNA expression of TFPI2 was decreased because less TFPI2 was bound by YTHDF1 39 . These earlier studies suggest that the effects of FTO-mediated m6A de-modification on RNA expression depend on the m6A readers.…”

Section: Discussionmentioning

confidence: 99%

KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2

Zhang,

Wu,

Zhang

et al. 2024

Commun Biol

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Potassium Channel Tetramerization Domain Containing 15 (KCTD15) participates in the carcinogenesis of several solid malignancies; however, its role in colorectal cancer (CRC) remains unclear. Here we find that KCTD15 exhibits lower expression in CRC tissues as compared to para-carcinoma tissues. Tetracycline (tet)-induced overexpression and knockdown of KCTD15 confirms KCTD15 as an anti-proliferative and pro-apoptotic factor in CRC both in vitro and in xenografted tumors. N6-methyladenosine (m6A) is known to affect the expression, stabilization, and degradation of RNAs with this modification. We demonstrate that upregulation of fat mass and obesity-associated protein (FTO), a classical m6A eraser, prevents KCTD15 mRNA degradation in CRC cells. Less KCTD15 RNA is recognized by m6A ‘reader’ YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) in FTO-overexpressed cells. Moreover, KCTD15 overexpression decreases protein expression of histone deacetylase 1 (HDAC1) but increases acetylation of critical tumor suppressor p53 at Lys373 and Lys382. Degradation of p53 is delayed in CRC cells post-KCTD15 overexpression. We further show that the regulatory effects of KCTD15 on p53 are HDAC1-dependent. Collectively, we conclude that KCTD15 functions as an anti-growth factor in CRC cells, and its expression is orchestrated by the FTO-YTHDF2 axis. Enhanced p53 protein stabilization may contribute to KCTD15’s actions in CRC cells.

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“…Moreover, in our results, a positive correlation was observed between PD-L1 and FTO, ZCCHC4, and HNRNPD, whereas PD-1 was negatively correlated with FTO, ZC3H7B, and HNRNPD. FTO is a known m6A demethylase that plays an important role in regulating RNA m6A methylation [ 28 ]. Previous studies have shown that overexpression of FTO in various tumors is associated with poor prognosis [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the prognostic potential of m6A methylation regulators in low-grade glioma: implications for tumor microenvironment modulation

Wu,

Chen,

et al. 2024

Eur J Med Res

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Background The biological behavior of low-grade glioma (LGG) is significantly affected by N6-methyladenosine (m6A) methylation, an essential epigenetic alteration. Therefore, it is crucial to create a prognostic model for LGG by utilizing genes that regulate m6A methylation. Methods Using TCGA and GTEx databases. We examined m6A modulator levels in LGG and normal tissues, and investigated PD-L1 and PD-1 expression, immune scores, immune cell infiltration, tumor immune microenvironment (TIME) and potential underlying mechanisms in different LGG clusters. We also performed immunohistochemistry and RT-qPCR to identify essential m6A adjustment factor. Results The results showed that m6A regulatory element expression was significantly increased in LGG tissues and was significantly associated with TMIE. A substantial increase in PD-L1 and PD-1 levels in LGG tissues and high-risk cohorts was observed. PD-L1 expression was positively correlated with FTO, ZCCHC4, and HNRNPD, whereas PD-1 expression was negatively correlated with FTO, ZC3H7B, and HNRNPD. The prognostic signature created using regulators of m6A RNA methylation was shown to be strongly associated with the overall survival of LGG patients, and FTO and ZCCHC4 were confirmed as independent prognostic markers by clinical samples. Furthermore, the results revealed different TIME characteristics between the two groups of patients, indicating disrupted signaling pathways associated with LGG. Conclusion Our results present that the m6A regulators play vital role in regulating PD-L1/PD-1 expression and the infiltration of immune cells, thereby exerting a sizable impact on the TIME of LGG. Therefore, m6A regulators have precise predictive value in the prognosis of LGG.

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m⁶A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2

Cited by 20 publications

References 50 publications

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2

Exploring the prognostic potential of m6A methylation regulators in low-grade glioma: implications for tumor microenvironment modulation

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m6A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2

Cited by 20 publications

References 50 publications

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

KCTD15 acts as an anti-tumor factor in colorectal cancer cells downstream of the demethylase FTO and the m6A reader YTHDF2

Exploring the prognostic potential of m6A methylation regulators in low-grade glioma: implications for tumor microenvironment modulation

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m⁶A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2