SLC9A5 promotes tumor growth and cell motility via ACOX1-mediated peroxisomal fatty acid oxidation

Growing evidence suggests a strong association between decreased lipid catabolism and the development of cancer. Solute carrier family 9 member A5 (SLC9A5) plays a regulatory role in colorectal function. However, the specific involvement of SLC9A5 in colorectal cancer (CRC) remains unclear, as well as its potential connection to lipid catabolism. We found that SLC9A5 exhibited significantly higher expression in CRC tumor tissues compared to adjacent paratumor tissues, as confirmed through analysis of the TCGA database and validation on a CRC tissue chip using IHC. Furthermore, in vitro experiments showed that knockdown of SLC9A5 resulted in suppressed cell proliferation, migration, and invasion. Then we performed bioinformatics analysis and found that SLC9A5 was significantly enriched in peroxisomal fatty acid oxidation (FAO) pathway and negatively correlated with its first rate-limiting enzyme acyl-CoA oxidases (ACOX). Interestingly, the expression of ACOX1, as well as FAO process indicated by changes in very long chain fatty acid levels, were enhanced upon SLC9A5 knockdown in CRC cells. Moreover, the attenuated tumor growth, migration, invasion, and increased FAO observed after SLC9A5 knockdown could be reversed by simultaneous knockdown of both SLC9A5 and ACOX1. In summary, these findings reveal the oncogenic role of SLC9A5 in CRC, particularly in relation to ACOX1-mediated peroxidation, and might serve as a promising therapeutic target for inhibiting the progression of colorectal cancer.