PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma.
PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma.
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DOI：
10.1126/sciadv.adf3566
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发表时间：
2023-08-02
期刊：
影响因子：
13.6
通讯作者：
Liu, Qiuli
中科院分区：
文献类型：
--
作者：
Peng, Song;Wang, Ze;Tang, Peng;Wang, Shuo;Huang, Yiqiang;Xie, Qiubo;Wang, Yapeng;Tan, Xintao;Tang, Tang;Yan, Xuzhi;Xu, Jing;Lan, Weihua;Wang, Luofu;Zhang, Dianzheng;Wang, Bin;Pan, Tiejun;Qin, Jun;Jiang, Jun;Liu, Qiuli
对于透明细胞肾细胞癌（ccRCC），脂质沉积在其发生、转移和耐药过程中起重要作用。然而，ccRCC中脂质沉积的分子机制在很大程度上仍然未知。通过无偏倚的CRISPR-Cas9筛选，我们发现表观遗传调控因子植物同源结构域手指蛋白8 （PHF8）是ccRCC脂质沉积的重要调控因子。此外，PHF8受von Hippel-Lindau (VHL)/hypoxia inducible factor （HIF）轴的调控，是VHL缺乏诱导的脂质沉积所必需的。PHF8转录上调谷氨酸氨连接酶（GLUL），促进脂质沉积和ccRCC进展。机制上，通过与c-MYC形成复合物，PHF8以组蛋白去甲基化依赖的方式上调TEA结构域转录因子1 （TEAD1）。随后，TEAD1通过转录上调GLUL。l-蛋氨酸亚砜对GLUL的药理抑制不仅抑制了ccRCC的脂质沉积和肿瘤生长，而且增强了依维莫司的抗癌作用。因此，PHF8-GLUL轴代表了ccRCC治疗的潜在治疗靶点。靶向PHF8/TEAD1/GLUL轴通过抑制脂质沉积和肿瘤进展代表了ccRCC的治疗靶点。
For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel–Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency–induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation–dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l-methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment. Targeting PHF8/TEAD1/GLUL axis represents a therapeutic target for ccRCC by inhibiting lipid deposition and tumor progression.
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影响因子：
14.9
作者：
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DOI：
10.1016/j.bbrc.2018.01.049
发表时间：
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影响因子：
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作者：
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