LNX1 Contributes to Cell Cycle Progression and Cisplatin Resistance

SIMPLE SUMMARY: The ligand of numb-protein X1 (LNX1) is reported to be upregulated in various cancers, however the cellular function of LNX1 is not clearly characterized. The aim of the present study was to elucidate the regulation of LNX1 expression and clarify the role of LNX1 in cell-cycle progression and resistance to the cancer therapeutic agent, cisplatin. We found that LNX1 expression is decreased by DNA damage including cisplatin treatment and the levels of S and G2/M populations were correlated with LNX1 expression. We also showed that the upregulation of LNX1 contributes to cell-cycle progression and cisplatin resistance. Our data suggest that LNX1 is the important regulator of the cell cycle, and contributes to tumor progression. ABSTRACT: The ligand of numb-protein X1 (LNX1) acts as a proto-oncogene by inhibiting p53 stability; however, the regulation of LNX1 expression has not been investigated. In this study, we screened chemicals to identify factors that potentially regulate LNX1 expression. We found that LNX1 expression levels were decreased by DNA damage, including that by cisplatin. Upon treatment with lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA), LNX1 expression levels increased. In addition, cell-cycle progression increased upon LNX1 expression; the levels of S and G2/M populations were correlated with LNX1 expression. Moreover, in CRISPR-Cas9-mediated LNX1 knockout cells, we observed a delay in cell-cycle progression and a downregulation of genes encoding the cell-cycle markers cyclin D1 and cyclin E1. Finally, the upregulation of LNX1-activated cell-cycle progression and increased resistance to cisplatin-mediated cell death. Taken together, these results suggest that LNX1 contributes to cell-cycle progression and cisplatin resistance.