FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability.
FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability.
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DOI：
10.7150/ijbs.77774
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发表时间：
2022
影响因子：
9.2
通讯作者：
Gong K
中科院分区：
文献类型：
--
作者：
Xu Y;Zhou J;Li L;Yang W;Zhang Z;Zhang K;Ma K;Xie H;Zhang Z;Cai L;Gong Y;Gong K
肾透明细胞癌(CcRCC)的进展仍然是临床实践中的一大挑战，阐明恶性进展的分子驱动因素对于开发有效的治疗靶点至关重要。最近的研究表明，N6-甲基腺苷(M6A)是真核生物中含量最丰富的基因修饰，在肿瘤的发生和发展中起着关键作用。然而，m6A介导的自噬在肿瘤尤其是肾细胞癌中的生物学作用和潜在机制尚不清楚。采用m6A斑点杂交、m6A RNA甲基化检测试剂盒和免疫荧光分析等方法检测组织标本中m6A水平及其与自噬通量的关系。通过生物信息学分析、实时定量聚合酶链式反应、免疫印迹、免疫组织化学等方法检测脂肪组织和肥胖相关蛋白(FTO)的表达模式及临床意义。用RNA-seq、MERIP-seq、MERIP-qRT-PCR、RIP-qRT-PCR、透射电子显微镜、免疫荧光分析和荧光素酶报告实验研究FTO-自噬的机制。在体外和体内评价FTO和自噬在肾细胞癌进展中的作用。在此，我们发现ccRCC中M6A修饰被抑制，并与自噬通量密切相关。升高的FTO被雷帕霉素抑制，而沉默的FTO增加了自噬通量，并削弱了ccRCC的生长和转移。SIK2被确定为m6A介导的自噬的功能靶点，从而促使FTO通过m6A-IGF2BP2依赖的机制在抑制自噬和促进肿瘤发生中发挥保守而重要的作用。此外，靶向FTO的小分子抑制剂FB23-2抑制了患者来源的异种移植(PDX)模型小鼠的肿瘤生长和延长了生存时间，表明FTO是治疗CCRCC的潜在有效靶点。我们的发现揭示了FTO/自噬/SIK2轴在调控ccRCC进展中的关键作用，提示FTO可能是ccRCC中一个有价值的预后生物标志物和有前途的治疗靶点。
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.
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影响因子：
64.8
作者：
Han, Zhifu;Niu, Tianhui;Chai, Jijie
通讯作者：
Chai, Jijie
急性髓性白血病中致癌 FTO 去甲基酶的小分子靶向
影响因子：
50.3
作者：
Huang, Yue;Su, Rui;Yang, Cai-Guang
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影响因子：
9.7
作者：
Gao, Tian;Zhang, Xiaohong;Liu, Shujuan
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Liu, Shujuan
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50.5
作者：
Ho, T. H.;Serie, D. J.;Eckel-Passow, J. E.
通讯作者：
Eckel-Passow, J. E.
影响因子：
50.3
作者：
Li Z;Weng H;Su R;Weng X;Zuo Z;Li C;Huang H;Nachtergaele S;Dong L;Hu C;Qin X;Tang L;Wang Y;Hong GM;Huang H;Wang X;Chen P;Gurbuxani S;Arnovitz S;Li Y;Li S;Strong J;Neilly MB;Larson RA;Jiang X;Zhang P;Jin J;He C;Chen J
通讯作者：
Chen J