OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and regulates its sensitivity to ferroptosis.
OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and regulates its sensitivity to ferroptosis.
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DOI：
10.1016/j.isci.2023.108148
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发表时间：
2023-11-17
期刊：
影响因子：
5.8
通讯作者：
Qin, Chao
中科院分区：
文献类型：
--
作者：
Yang, Zhou;Wei, Xiyi;Ji, Chengjian;Ren, Xiaohan;Su, Wei;Wang, Yichun;Zhou, Jingwan;Zhao, Zheng;Zhou, Pengcheng;Zhao, Kejie;Yao, Bing;Song, Ninghong;Qin, Chao
O-GlcNAc转移酶(OGT)在多种肿瘤的发生发展中起作用，但其在肾透明细胞癌(CcRCC)中的作用尚不清楚。在这项研究中，我们发现OGT在ccRCC中上调，这种上调与较差的生存相关。此外，OGT还能促进VHL突变的ccRCC细胞的增殖、克隆形成和侵袭。在机制上，OGT通过抑制泛素-蛋白酶体系统介导的降解，增加了低氧诱导因子-2α(HIF-2α)(透明细胞表型的主要驱动因素)的蛋白水平。有趣的是，OGT/HIF-2α轴赋予肾细胞癌对铁性下垂的高度敏感性。综上所述，OGT通过抑制HIF-2α的降解来促进肾小管上皮细胞癌的进展，能够调节OGT/HIF-2α轴的药物可能对突变的肾小管上皮细胞癌发挥治疗作用。OGT主要在VHL突变的ccRCC HIF-2a中发挥致癌作用，而不是HIF-1a，是OGT的主要靶点VHL突变的ccRCC OGT以O-GlcNAc非依赖的方式促进HIF-2a的蛋白质稳定性OGT增加VHL突变的ccRCC对铁下垂的敏感性分子生物学实验方法；分子网络；体外毒理学；细胞生物学的功能方面；癌症
O-GlcNAc transferase (OGT) acts in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC and this upregulation was associated with a worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasion of VHL-mutated ccRCC cells. Mechanistically, OGT increased the protein level of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis conferred ccRCC a high sensitivity to ferroptosis. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α, and agents that can modulate the OGT/HIF-2α axis may exert therapeutic effects on mutated VHL ccRCC. OGT plays oncogenic role mainly in VHL-mutated ccRCC HIF-2a, but not HIF-1a, is the main target of OGT VHL-mutated ccRCC OGT promotes protein stability of HIF-2a in O-GlcNac independent manner OGT increases the sensitivity of VHL-mutated ccRCC to ferroptosis Molecular biology experimental approach; Molecular network; In vitro toxicology; Functional aspects of cell biology; Cancer
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影响因子：
9
作者：
Seo HG;Kim HB;Yoon JY;Kweon TH;Park YS;Kang J;Jung J;Son S;Yi EC;Lee TH;Yang WH;Cho JW
通讯作者：
Cho JW
DOI：
10.1073/pnas.1602883113
发表时间：
2016-04-05
影响因子：
11.1
作者：
Zhang, Chuanzhao;Samanta, Debangshu;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
82.9
作者：
Choueiri, Toni K.;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
16.6
作者：
Hoefflin, Rouven;Harlander, Sabine;Frew, Ian J.
通讯作者：
Frew, Ian J.
影响因子：
16
作者：
Ferrer, Christina M.;Lynch, Thomas P.;Sodi, Valerie L.;Falcone, John N.;Schwab, Luciana P.;Peacock, Danielle L.;Vocadlo, David J.;Seagroves, Tiffany N.;Reginato, Mauricio J.
通讯作者：
Reginato, Mauricio J.