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

Abstract

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.