Inhibiting Cyclin‐Dependent Kinase 13‐Mediated Nuclear Ubiquitous Casein Kinase and Cyclin‐Dependent Kinase Substrate 1 Phosphorylation Facilitates Oxidative Stress‐Induced Apoptosis in Melanoma

Cellular responses after oxidative stress‐induced deoxyribonucleic acid (DNA) damage (e.g., DNA double‐strand break) control tumor cell proliferation, senescence, and apoptosis. The nuclear ubiquitous casein kinase and cyclin‐dependent kinase substrate 1 (NUCKS1) ensures replication feasibility by modulating double‐strand break repair necessary to regulate tumor cell proliferation. However, the regulatory mechanism of NUCKS1 in oxidative stress‐induced melanoma cell apoptosis is not well characterized. In this study, we reported reduced phosphorylation of NUCKS1 during oxidative stress‐mediated melanoma A375 and A875 cell apoptosis, and silencing of NUCKS1 obviously promoted A375 and A875 cell apoptosis. Mechanistically, cyclin‐dependent kinase 13 (CDK13) was identified as a major upstream kinase to phosphorylate NUCKS1 and downregulated via ataxia telangiectasia mutated (ATM)/checkpoint kinase 2 (Chk2)/cell division cycle 25C (Cdc25C) axis during the process of oxidative stress‐induced apoptosis. Moreover, we found that p‐NUCKS1 could bind to tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein Zeta (YWHAZ) and subsequently regulate the level of BCL2‐associated X (Bax), thereby leading to melanoma A375 and A875 cell apoptosis. Furthermore, we found that p‐NUCKS1 was highly expressed in tumor specimens from melanoma patients, and silencing of NUCKS1 inhibited tumor growth in melanoma A375 and A875‐bearing mouse models. Therefore, p‐NUCKS1 could act as a potential target for melanoma treatment by mediating oxidative stress‐induced apoptosis.