Abstract
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.
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This study was partially supported by The National Natural Science Foundation of China (No. 82072842, 81972411, 81902573 and 81970216), and The Natural Science Foundation of Hebei Province (H2020206601, H2022206185).
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ZY, CQ and YZ carry out the design and conception. ZY, XC, HG ZH and BS carry out the methodology. YZ, ZH, JG, CZ, and YZ carry out the acquisition of the data. YZ, XC, ZY, JW and ZH carry out analysis and interpretation of the data. DW, HG, BS, and JG carry out animal models. ZY, XC, JW, and YZ carry out writing, review, and/or revision of the manuscript. All authors read and approved the final manuscript.
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Zhang, Y., Chen, XN., Zhang, H. et al. CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA. Cell Death Differ 30, 2462–2476 (2023). https://doi.org/10.1038/s41418-023-01223-z
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DOI: https://doi.org/10.1038/s41418-023-01223-z