NAT10 promotes metastasis through enhancer remodeling of cancer cells

Abstract Distant organ metastases account for the majority of the cancer-related death. However, the detailed mechanism underlying the metastatic potential of cancer cells is poorly understood. We have previously shown than NUP210-dependent nuclear pore-associated chromatin-bound protein complex is involved in cellular mechanotransduction and metastasis in breast cancer. Although NAT10, an RNA cytidine acetyl transferase has been shown to interact with this protein complex, specific function of NAT10 in metastasis is not well understood. Using allograft and genetically engineered highly metastatic PyMT mouse model, we found that the loss of NAT10 significantly decreases lung metastasis in mice. NAT10 is mainly localized to the nucleolus and nucleoplasmic compartment of the cancer cells. Current understanding suggests a role of NAT10 in acetylation of mRNAs and ribosomal RNAs. In contrast to its role as an RNA acetylase, we uncovered a new mechanism of NAT10 in cancer cells. Using co-immunoprecipitation followed by mass spectrometry and chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we found that NAT10 is interacting with super-enhancer associated protein complex. RNA-seq analysis revealed that the loss of NAT10 leads to dramatic transcriptional suppression of super-enhancer driven genes including MYC. Mechanistically, using mass spectrometry-based quantification of protein acetylation, we showed that the loss of NAT10 leads to decreased acetylation of enhancer-associated Histone H4 and H3 modification. NAT10 loss also leads to increased heterochromatin-forming histone methylation within the cell nuclei. Our study revealed a distinct role of NAT10 as an enhancer remodeler in metastatic cancer cells. Therefore, NAT10 could be a potential therapeutic target in preventing metastatic disease. Citation Format: Ruhul Amin, Ngoc-Han Ha, Jordan L. Meier, Kent W. Hunter. NAT10 promotes metastasis through enhancer remodeling of cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A012.