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

ABSTRACT: The aberrant expression of fat mass and obesity-associated protein (FTO) has been confirmed to be associated with a variety of cancers and participates in the regulation of multiple biological behaviours. FTO plays an oncogenic role in bladder cancer, but few studies have focused on how FTO promotes bladder cancer progression by regulating miRNA synthesis. Here, we confirmed that FTO expression was significantly increased in bladder cancer and was associated with a poor prognosis. FTO overexpression promoted bladder cancer cell proliferation, whereas FTO knockdown inhibited bladder cancer cell proliferation. We also demonstrated that FTO promoted bladder cancer cell proliferation via the FTO/miR-576/CDK6 pathways. Taken together, our work revealed that FTO plays a critical role in bladder cancer and could be a potential diagnostic or prognostic biomarker for this disease.

SUBMITTER: Zhou G

PROVIDER: S-EPMC8560827 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Zhou Guanwen G Yan Keqiang K Liu Jikai J Gao Lijian L Jiang Xianzhou X Fan Yidong Y

Cell death discovery 20211101 1

The aberrant expression of fat mass and obesity-associated protein (FTO) has been confirmed to be associated with a variety of cancers and participates in the regulation of multiple biological behaviours. FTO plays an oncogenic role in bladder cancer, but few studies have focused on how FTO promotes bladder cancer progression by regulating miRNA synthesis. Here, we confirmed that FTO expression was significantly increased in bladder cancer and was associated with a poor prognosis. FTO overexpres ...[more]

PMID: 34725345

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Project description:BackgroundLung cancer (LC) occupies an important position in the lethality of cancer patients. Acquired resistance to gefitinib in lung adenocarcinoma (LUAD) seriously affects the therapeutic efficacy of LC. Thus, it is of major scientific and clinical significance to probe the mechanism of gefitinib resistance in LUAD for ameliorating the prognosis of patients.MethodsThe expression of miRNAs in gefitinib-resistant LUAD cells was validated using qRT-PCR. Cell viability was assessed through CCK-8, whereas cell death was examined through PI staining. Changes in the ferroptosis process were evaluated by detecting the intracellular Glutathione (GSH), Malondialdehyde (MDA), and Reactive Oxygen Species (ROS) levels. Downstream targets of miR-138-5p were verified via luciferase reporter and RNA pull-down assays. RIP and qRT-PCR were employed to evaluate pri-miR-138-5p binding to DiGeorge critical region 8 (DGCR8) and the pri-miR-138-5p m6A modification level. Additionally, the impact of fat mass and obesity-associated protein (FTO) on LUAD gefitinib sensitivity was assessed in vivo by constructing a xenograft model.ResultsWe observed that miR-138-5p was notably diminished in gefitinib-resistant cells. Overexpression of miR-138-5p suppressed viability while facilitated cell death and intracellular ferroptosis in gefitinib-resistant cells. Moreover, lipocalin 2 (LCN2) was the downstream target of miR-138-5p. The biological functions of miR-138-5p on gefitinib-resistant cells was reversed by introduction of LCN2. FTO suppressed the binding of DGCR8 to pri-miR-138-5p through m6A modification, thereby restraining the processing of miR-138-5p. Meanwhile, silencing of FTO enhanced the sensitivity of LUAD to gefitinib treatment.ConclusionFTO suppressed the processing of miR-138-5p and then modulated the proliferation, death, and ferroptosis of gefitinib-resistant cells through the miR-138-5p/LCN2 pathway, which may put forward novel insights for clinically ameliorating the therapeutic effect of gefitinib in LUAD.

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Dataset Information

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

Publications

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

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