FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability

作者：Yawei Xu, Jingcheng Zhou, Lei Li, Wuping Yang, Zedan Zhang, Kenan Zhang, Kaifang Ma, Haibiao Xie, Zheng Zhang, Lin Cai, Yanqing Gong, Kan Gong · 发表于：International Journal of Biological Sciences · 年份：2022 · DOI：10.7150/ijbs.77774 · 被引用次数：108 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Autophagy in Disease and Therapy

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 N 6 -methyladenosine (m 6 A) 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 m 6 A-mediated autophagy in cancers especially in ccRCC remain poorly elucidated. m 6 A dot blot assay, m 6 A RNA methylation assay kit and immunofluorescence analysis were used to profile m 6 A 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 m 6 A 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...