Dataset Information

FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m⁶A dependent pathway.

ABSTRACT: FTO, as an m⁶A mRNA demethylase, is involved in various cancers. However, the role of FTO in clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, we discovered FTO is upregulated in ccRCC. Functionally, knockdown of FTO significantly impairs the proliferation and migration ability of ccRCC cells. Mechanistically, our data suggest FTO promotes the proliferation and migration of ccRCC through preventing degradation of PDK1 mRNA induced by YTHDF2 in an m⁶A-dependent mechanism. Overall, our results identify the protumorigenic role of FTO through the m⁶A/YTHDF2/PDK1 pathway, which could be a promising therapeutic target for ccRCC.

SUBMITTER: Shen H

PROVIDER: S-EPMC9374762 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m6A dependent pathway.

Shen Haixiang H Ying Yufan Y Ma Xueyou X Xie Haiyun H Chen Shiming S Sun Jiazhu J Liu Zixiang Z Wen Chao C Yang Zitong Z Wang Xiao X Xu Mingjie M Luo Jindan J Liu Ben B Li Jiangfeng J Zheng Xiangyi X Zheng Xiangyi X Xie Liping L

Cell death discovery 20220812 1

FTO, as an m6A mRNA demethylase, is involved in various cancers. However, the role of FTO in clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, we discovered FTO is upregulated in ccRCC. Functionally, knockdown of FTO significantly impairs the proliferation and migration ability of ccRCC cells. Mechanistically, our data suggest FTO promotes the proliferation and migration of ccRCC through preventing degradation of PDK1 mRNA induced by YTHDF2 in an m6</ ...[more]

PMID: 35961973

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Project description:The progression of clear cell renal cell carcinoma (ccRCC) remains a major challenge in clinical practice, and elucidation of the molecular drivers of malignancy progression is critical for the development of effective therapeutic targets. Recent studies have demonstrated that N6-methyladenosine (m6A) is the most abundant modification of eukaryotic mRNA and plays a key role in tumorigenesis and progression. However, the biological roles and underlying mechanisms of m6A-mediated autophagy in cancers especially in ccRCC remain poorly elucidated. m6A dot blot assay, m6A RNA methylation assay kit and immunofluorescence analysis were used to profile m6A levels in tissue samples and their correlation with autophagic flux. Expression patterns and clinical significance of fat mass and obesity-associated protein (FTO) were determined through bioinformatics analysis, real-time PCR, western blotting, immunohistochemistry. RNA-seq, MeRIP-seq, MeRIP-qRT-PCR, RIP-qRT-PCR, transmission electron microscopy, immunofluorescence analysis and luciferase reporter assay were used to investigate the underlying mechanism of the FTO-autophagy axis. The role of FTO and autophagy in ccRCC progression was evaluated both in vitro and in vivo. Here we found that m6A modification was suppressed and closely related to autophagic flux in ccRCC. Elevated FTO was inhibited by rapamycin, whereas silencing FTO enhanced autophagic flux and impaired ccRCC growth and metastasis. SIK2 was identified as a functional target of m6A-mediated autophagy, thereby prompting FTO to play a conserved and important role in inhibiting autophagy and promoting tumorigenesis through an m6A-IGF2BP2 dependent mechanism. Moreover, the small molecule inhibitor FB23-2 targeting FTO inhibited tumor growth and prolonged survival in the patient-derived xenograft (PDX) model mice, suggesting that FTO is a potential effective therapeutic target for ccRCC. Our findings uncovered the crucial role of FTO/autophagy/SIK2 axis in modulating the progression of ccRCC, suggesting that FTO may serve as a valuable prognostic biomarker and promising therapeutic target in ccRCC.

Dataset Information

FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m⁶A dependent pathway.

Publications

FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m<sup>6</sup>A dependent pathway.

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