Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
Department of Urology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, P R China.
Cell Death Differ. 2023 Dec;30(12):2462-2476. doi: 10.1038/s41418-023-01223-z. Epub 2023 Oct 16.
Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.
细胞周期蛋白依赖性激酶（CDKs）调节细胞周期进程和许多基因的转录，包括脂质代谢相关基因，异常的脂质代谢参与前列腺癌的发生。先前的研究表明，CDK13 在前列腺癌（PCa）中的表达上调，脂肪酸合成增加。然而，CDK13 上调与 PCa 细胞中异常脂质代谢之间的分子机制在很大程度上仍然未知。在这里，我们表明 CDK13 在 PCa 细胞中的上调增加了脂肪酸链和脂质类，导致细胞内脂质沉积，这与乙酰辅酶 A 羧化酶（ACC1）的表达呈正相关，ACC1 是脂肪酸合成的第一个限速酶。获得和丧失功能研究表明，ACC1 通过增强脂质合成来介导 CDK13 诱导的脂质积累和 PCa 进展。在机制上，CDK13 与 RNA-甲基转移酶 NSUN5 相互作用，促进其丝氨酸 327 的磷酸化。反过来，磷酸化的 NSUN5 催化 ACC1 mRNA 的 m5C 修饰，然后 m5C 修饰的 ACC1 mRNA 与 ALYREF 结合，增强其稳定性和核输出，从而导致 ACC1 表达和 PCa 细胞中脂质沉积增加。总的来说，我们的结果揭示了 CDK13 在调节 ACC1 表达中的新功能，并确定了一个以前未被认识的 CDK13/NSUN5/ACC1 途径，该途径介导了 PCa 细胞中的脂肪酸合成和脂质积累，靶向这个新发现的途径可能是治疗 PCa 的一种新的治疗选择。
