FTO promotes tumour proliferation in bladder cancer via the FTO/miR-576/CDK6 axis in an m6A-dependent manner

Zhou, Guanwen; Kou, Yan; Liu, Ji‐Kai; Gao, Lijian; Jiang, Xianzhou; Fan, Yi‐Ming

doi:10.1038/s41420-021-00724-5

Cited by 36 publications

(29 citation statements)

References 34 publications

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“…FTO, considered as an N6-methyladenosine (m 6 A) demethylase, is discovered to play an oncogenic or tumor-suppressive role in multiple cancers [ 28 ]. One study showed FTO inhibited the progression of BCa [ 29 ], while other studies, consistent with our results, confirmed FTO played a role as an oncogene promoting proliferation and migration of BCa cell lines [ 30 – 32 ]. Zhou et al confirmed FTO regulated the cell cycle of BCa cell lines by indirectly targeting CDK6 via m 6 A modification, while they did not figure out the mechanism of migration promotion ability induced by FTO [ 32 ].…”

Section: Discussionsupporting

confidence: 91%

“…One study showed FTO inhibited the progression of BCa [ 29 ], while other studies, consistent with our results, confirmed FTO played a role as an oncogene promoting proliferation and migration of BCa cell lines [ 30 – 32 ]. Zhou et al confirmed FTO regulated the cell cycle of BCa cell lines by indirectly targeting CDK6 via m 6 A modification, while they did not figure out the mechanism of migration promotion ability induced by FTO [ 32 ]. MMP9 is an essential enzyme causing degradation of the basement membrane along with the extracellular matrix, regulating migration and metastasis of cancers [ 33 ].…”

Section: Discussionsupporting

confidence: 91%

“…Besides, we also found overexpressing miR-5581-3p downregulated the expression of MMP9 and CCND1, consistent with the results of silencing FTO. As an eraser of m 6 A modification, FTO has been reported to reduce the m 6 A level in BCa [ 30 – 32 ]. In this study, we confirmed silencing FTO or overexpressing miR-5581-3p would increase the m 6 A level in BCa, suggesting miR-5581-3p regulating the m 6 A modification via FTO.…”

Section: Discussionmentioning

confidence: 99%

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SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer

Sun

Ying

et al. 2022

Cell Death Discov.

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Previous research evidence suggests that microRNAs (miRNAs) play an indispensable role in onset and progression of bladder cancer (BCa). Here, we explored the functions and mechanisms of miR-5581-3p in BCa. miR-5581-3p, as a tumor suppressor in BCa, was detected at a lower expression level in BCa tissue and cells in contrast with the non-malignant bladder tissue and cells. Over-expression of miR-5581-3p remarkably dampened the migration and proliferation of BCa in vitro and in vivo. SMAD3 and FTO were identified as the direct targets of miR-5581-3p by online databases prediction and mRNA-seq, which were further verified. SMAD3 as a star molecule in modulating EMT progress of BCa had been formulated in former studies. Meanwhile, FTO proved as an N6-methyladenosine (m6A) demethylase in decreasing m6A modification was confirmed to regulate the migration and proliferation in BCa. In addition, we conducted rescue experiments and confirmed overexpressing miR-5581-3p partially rescued the effects of the overexpressing SMAD3 and FTO in BCa cells. In conclusion, our studies exhibit that miR-5581-3p is a novel tumor inhibitor of BCa.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer

Sun

Ying

et al. 2022

Cell Death Discov.

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“…Fat mass- and obesity-associated protein (FTO) was recently reported to participate in multiple tumorigenic processes including immune evasion in several malignant tumors ( Li et al, 2017 ; Zhao et al, 2020 ; Tao et al, 2021 ; Zhou et al, 2021 ), implying the therapeutic potential of FTO inhibition in treating multiple cancers. In this study, high FTO expression and low HDAC1 expression were both observed in patients with high EMD score ( Figure 8A ).…”

Section: Resultsmentioning

confidence: 99%

Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer

et al. 2022

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Emerging evidence has revealed the pivotal role of epigenetic modifications in shaping the tumor microenvironment (TME). However, crosstalk between different modification types and their clinical relevance in cancers remain largely unexplored. In this study, using ChIP/MeRIP-seq data of seven human gastric cell lines, we systematically characterized the crosstalk of four epigenetic modification types including H3K4me1, H3K4me3, H3K27ac, and N6-methyladenosine (m6A) and identified a recurrent subtype with high FTO expression and low HDAC1 expression across three independent gastric cancer (GC) cohorts, which we named the epigenetic-modification-dysregulated (EMD) subtype. Patients of the EMD subtype were featured with poor survival, stromal activation, and immune suppression. Extensive relevance to clinical characteristics was observed in the EMD subtype, including the Lauren classification, MSI status, histological grade, TNM stage, the Asian Cancer Research Group classification, and the immune/fibrotic classification. An EMD score was then constructed using WGCNA and ssGSEA algorithms, to precisely recognize the EMD subtype and indicate prognosis and response to immunotherapy in multiple independent GC cohorts. Correlations of the EMD score with tumor mutation burden, tumor purity, aneuploidy score, tumorigenic pathways, TME characteristics, and FTO/HDAC1 ratio were measured. In vitro experiments were performed to demonstrate the correlation between FTO and the epithelial–mesenchymal transition pathway, which suggested FTO as a targetable vulnerability for GC patients with a high EMD score. Altogether, by comprehensively analyzing the epigenetic modification patterns of 1518 GC patients, we identified a novel stromal-activated subtype with poor survival and resistance to immunotherapy, which might benefit from the combined immune checkpoint inhibition therapy with FTO inhibition.

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“…RNA m6A methylation is controlled by METTL3, METTL14, WTAP, RBM15 RBM15B, and Cbl proto-oncogene E3, and is catalyzed by methyltransferase complexes composed of CBLL1, VIRMA, and ZC3H13. Of these proteins, METTL3 and METTL14 exhibit m6A methyltransferase activity ( Zhou et al, 2021a ; Maldonado Lopez and Capell 2021 ; Pan et al, 2021 ). WTAP promotes m6A functionby recruiting METTL3 and METTL14 into nuclear speckles ( Deng et al, 2021 ).…”

Section: M6a Roles and Disease Mechanismsmentioning

confidence: 99%

Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

Liu

2022

Front. Genet.

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N6-methyladenosine (m6A) is a dynamic, reversible post-transcriptional modification, and the most common internal modification of eukaryotic messenger RNA (mRNA). Considerable evidence now shows that m6A alters gene expression, thereby regulating cell self-renewal, differentiation, invasion, and apoptotic processes. M6A methylation disorders are directly related to abnormal RNA metabolism, which may lead to tumor formation. M6A methyltransferase is the dominant catalyst during m6A modification; it removes m6A demethylase, promotes recognition by m6A binding proteins, and regulates mRNA metabolic processes. Bladder cancer (BC) is a urinary system malignant tumor, with complex etiology and high incidence rates. A well-differentiated or moderately differentiated pathological type at initial diagnosis accounts for most patients with BC. For differentiated superficial bladder urothelial carcinoma, the prognosis is normally good after surgery. However, due to poor epithelial cell differentiation, BC urothelial cell proliferation and infiltration may lead to invasive or metastatic BC, which lowers the 5-years survival rate and significantly affects clinical treatments in elderly patients. Here, we review the latest progress in m6A RNA methylation research and investigate its regulation on BC occurrence and development.

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FTO promotes tumour proliferation in bladder cancer via the FTO/miR-576/CDK6 axis in an m6A-dependent manner

Cited by 36 publications

References 34 publications

SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer

SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer

Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer

Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

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