Remodelin, a N‐acetyltransferase 10 (NAT10) inhibitor, alters mitochondrial lipid metabolism in cancer cells

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.

NAT10: An RNA cytidine transferase regulates fatty acid metabolism in cancer cells

“…Remodelin, a small molecular inhibitor of NAT10 on cancer cells. 12 Pathway analysis showed a similar pattern with enrichment analysis based on significance. The most significant pathways from the identified lipid species were FA biosynthesis, beta-oxidation of VLCFA and ketone body metabolism (Figure 7E).…”

“…The cellular lipid content of transfected and palmitate load cells was measured via Oil Red O staining (Sigma, USA) 12 . After 24 h, transfected and palmitate‐loaded cells were washed two times with PBS, fixed in 10% formalin for 30 min, followed by staining with Oil Red O and then incubated for an additional 30 min at room temperature.…”

“…11 Although many information point to the impact of NAT10-dependent ac4C modification on different cancer mechanisms, knowledge of the impact of NAT10 in pathways is still obscure. Recently, we reported the effect of Remodelin, the only known small molecule inhibitor of NAT10 on mitochondrial lipid metabolism 12 . With this information, we decided to explore and identify pathways that are regulated through NAT10-dependent ac4C RNA acetylation.…”

The roles and mechanisms of epigenetic regulation in pathological myocardial remodeling

“…Recently, a few activators or inhibitors of m6A enzymes including METTL3-METTL14 complex have also been developed (187,188). Remodelin, a small molecule inhibitor of NAT10, was reported to alleviate cancers or inflammatory diseases (189,190). However, the effectiveness of these compounds in CVDs remain to be demonstrated in the future.…”

Inhibition of N-Acetyltransferase 10 Suppresses the Progression of Prostate Cancer through Regulation of DNA Replication

“…Remodelin, an inhibitor of NAT10 that is primarily used to relieve nuclear lamina defect-induced phenotypes, has been demonstrated to suppress a variety of human cancer cells, inhibiting their growth and cell cycle progression [ 12 , 13 , 14 ]. Our recent investigation further revealed that the inhibitory effects of Remodelin rely on the functional activity of NAT10 during DNA replication [ 15 ].…”