Renal Division, Department of Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Core Competence Metabolomics, Hilde-Mangold-Haus, University of Freiburg, 79104 Freiburg, Germany.
Cells. 2023 Mar 8;12(6):835. doi: 10.3390/cells12060835.
Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer, and inactivation of the VHL tumor suppressor gene is found in almost all cases of hereditary and sporadic ccRCCs. CcRCC is associated with the reprogramming of fatty acid metabolism, and stearoyl-CoA desaturases (SCDs) are the main enzymes controlling fatty acid composition in cells. In this study, we report that mRNA and protein expression of the stearoyl-CoA desaturase SCD5 is downregulated in -deficient cell lines. Similarly, in mutants, FAT-7/SCD5 activity is repressed, supporting an evolutionary conservation. SCD5 regulation by VHL depends on HIF, and loss of SCD5 promotes cell proliferation and a metabolic shift towards ceramide production. In summary, we identify a novel regulatory function of VHL in relation to SCD5 and fatty acid metabolism, and propose a new mechanism of how loss of VHL may contribute to ccRCC tumor formation and progression.
透明细胞肾细胞癌（ccRCC）是最常见的肾癌组织学亚型，几乎所有遗传性和散发性 ccRCC 病例中都发现了 VHL 肿瘤抑制基因失活。ccRCC 与脂肪酸代谢的重编程有关，而硬脂酰辅酶 A 去饱和酶（SCDs）是控制细胞中脂肪酸组成的主要酶。在这项研究中，我们报告说，在 -缺陷细胞系中，硬脂酰辅酶 A 去饱和酶 SCD5 的 mRNA 和蛋白表达下调。同样，在 突变体中，FAT-7/SCD5 活性受到抑制，支持了进化保守性。VHL 对 SCD5 的调节依赖于 HIF，而 SCD5 的缺失促进了细胞增殖和代谢向神经酰胺生成的转变。总之，我们确定了 VHL 与 SCD5 和脂肪酸代谢相关的新的调节功能，并提出了 VHL 缺失如何可能有助于 ccRCC 肿瘤形成和进展的新机制。
