Bestatin inhibits the development of cutaneous melanoma by inhibiting the expression of LTA4H.

OBJECTIVE

In this study, we used Mendelian randomization analysis to explore the causal relationships between drug targets and cutaneous melanoma (CM) and subsequently screened for new drug targets for CM. In addition, we verified whether targeted drugs could inhibit the development of CM in CM cells by suppressing the expression of target genes.

METHODS

The eQTL data of 2,664 drug target genes (exposures) were sourced from the eQTLGen database. The GWAS summary data for CM (outcome) were obtained from the UK Biobank and FinnGen databases. The inverse-variance weighted (IVW) model was used as the primary analytical method. For the cell experiments, we first conducted RT-PCR and western blot analyses in three CM cell lines to validate the expression of LTA4H. LTA4H was subsequently knocked down and overexpressed in CM cell lines, and the proliferation, migration, invasion, and apoptosis of CM cells were evaluated. Finally, bestatin was used to stimulate CM cells to examine its effect on their malignant functions.

RESULTS

MR, GEO2R, and PheWAS analyses revealed that high expression of LTA4H can promote the development of CM. In cell experiments, compared with normal fibroblasts, melanoma cells highly expressed LTA4H. Moreover, after LTA4H was knocked down in SK-MEL-28 cells, their malignant functions decreased. After LTA4H was overexpressed in A-375 cells, the degree of malignancy increased. Finally, bestatin inhibited the malignancy of A-375 cells through the regulation of LTA4H.

CONCLUSION

In this study, MR analysis revealed that high expression of LTA4H can promote the occurrence of CM. In addition, the results of the cell experiments revealed that bestatin can inhibit the development of melanoma cells by reducing the expression of LTA4H.