PHF8-GLUL轴在清除型肾细胞癌的脂质堆积和肿瘤生长中的作用。
PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma.
发表日期：2023 Aug 02
作者：
Song Peng, Ze Wang, Peng Tang, Shuo Wang, Yiqiang Huang, Qiubo Xie, Yapeng Wang, Xintao Tan, Tang Tang, Xuzhi Yan, Jing Xu, Weihua Lan, Luofu Wang, Dianzheng Zhang, Bin Wang, Tiejun Pan, Jun Qin, Jun Jiang, Qiuli Liu
来源：
Epigenetics & Chromatin
摘要：
对于清晰细胞肾细胞癌（ccRCC），脂质沉积在其发展、转移和耐药性中起到重要作用。然而，ccRCC中脂质沉积的分子机制仍然大部分未知。通过进行无偏CRISPR-Cas9筛选，我们鉴定出表观遗传调节因子植物顶级结构域指蛋白8（PHF8）作为ccRCC脂质沉积的重要调节因子。此外，PHF8受von Hippel-Lindau（VHL）/缺氧诱导因子（HIF）轴的调控，并且对VHL缺陷诱导的脂质沉积至关重要。PHF8通过转录上调谷氨酰胺合酶（GLUL），促进脂质沉积和ccRCC的进展。在机制上，PHF8与c-MYC形成复合物，以组蛋白去甲基化依赖方式上调TEA结构域转录因子1（TEAD1）。随后，TEAD1转录上调GLUL。通过使用L-甲硫氨酮对GLUL进行药理学抑制，不仅抑制了ccRCC的脂质沉积和肿瘤生长，还增强了依维莫司的抗肿瘤效果。因此，PHF8-GLUL轴代表了ccRCC治疗的潜在治疗靶点。
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.