Remodelin, a N‐acetyltransferase 10 (NAT10) inhibitor, alters mitochondrial lipid metabolism in cancer cells. Issue 12 (4th October 2021)

• Record Type: Journal Article
• Authors: Dalhat, Mahmood Hassan; Mohammed, Mohammed Razeeth Shait; Ahmad, Abrar; Khan, Mohammad Imran; Choudhry, Hani
• Is Part Of: Journal of cellular biochemistry. Volume 122:Issue 12(2021)
• Page Start: 1936
• Page End: 1945
• Publication Date: 2021-10-04
• Subjects: cancer -- metabolomics -- NAT10 -- remodelin; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.30155
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: Remodelin is a small molecule inhibitor of N‐acetyltransferase 10 (NAT10), reported to reverse the effect of cancer conditions such as epithelial to mesenchymal transition, hypoxia, and drug resistance. We analysed RNA seq data of siNAT10 and found many metabolic pathways were altered, this made us perform unbiased metabolic analysis. Here we performed untargeted metabolomics in Remodelin treated cancer cells using high‐performance liquid chromatography‐tandem mass spectrometry. Statistical analysis revealed a total number of 138 of which 52 metabolites were significantly modified in Remodelin treated cells. Among the most significantly altered metabolites, we identified metabolites related with mitochondrial fatty acid elongation (MFAE) and mitochondrial beta‐oxidation such as lauroyl‐CoA, cholesterol, triglycerides, (S)−3‐hydroxyhexadecanoyl‐CoA, and NAD + . Furthermore, assessment showed alteration in expression of Enoyl‐CoA hydratase, short chain 1, mitochondrial ( ECHS1 ), and Mitochondrial trans‐2‐enoyl‐CoA reductase ( MECR ) genes, associated with MFAE pathway. We also found statistically significant decrease in total cholesterol and triglycerides in Remodelin treated cancer cells. Overall, our results showed that Remodelin alters mitochondrial fatty acid metabolism and lipid accumulation in cancer cells. Finally, we validated these results in NAT10 knockdown cancer cells and found that NAT10 reduction results in alteration in gene expression associated with mitochondrial fatty acid metabolism, clearly suggesting the possible role of NAT10 in maintaining mitochondrial fatty acid metabolism.