Deoxyribonuclease 1 Like 3 (DNASE1L3) is a member of the deoxyribonuclease I family that is associated with some diseases, including systemic lupus erythematosus and hypocomplementemic urticarial vasculitis. Recently, abnormal DNASE1L3 was preliminarily shown to correlate with tumor pathogenesis. However, its role is still undetermined in nasopharyngeal carcinoma (NPC). Multiple sets of Gene Expression Omnibus (GEO) high-throughput data were utilized to screen the differentially expressed genes. Signal pathway enrichment analysis analyzed the correlation between DNASE1L3 and epithelial-mesenchymal transition (EMT) and cytoskeleton reorganization. An immunohistochemistry assay for analysis of DNASE1L3 expression was used to detect the clinical samples. Woundhealing, migration, invasion assays, and mouse model of lung metastasis were used to assess the role of DNASE1L3 in NPC metastasis. The mechanism of DNASE1L3 inhibition of NPC metastasis by attenuating MYH9/β-catenin/c-Jun/LncRNA-KDM4A-induced E-cadherin ubiquitination degradation was demonstrated by protein stability evaluation, co-immunoprecipitation, immunofluorescence, chromatin immunoprecipitation, dual-luciferase reporter assay, and RNA immunoprecipitation. DNASE1L3 downregulation in patients with NPC was not only negatively related to lymph node metastasis and distant metastasis but was also positively associated with poor prognosis. Overexpression of DNASE1L3 in NPC cells suppresses migration, invasion, and metastasis in vitro and in vivo. Inversely, DNASE1L3 knockdown increased cell migration and invasion abilities. Mechanistically, DNASE1L3 recruited PARK2 to ubiquitinate and degrade MYH9 protein. MYH9 protein activated β-catenin/c-Jun signal and augmented c-Jun-induced LncRNA-KDM4A transcription. In the process of DNASE1L3-induced metastatic suppression, decreased LncRNA-KDM4A attenuated the recruitment of E3 ubiquitin ligase Hakai and thus impeded the degradation of E-cadherin, by which heightened E-cadherin protein stability and finally inactivated the EMT signal. Our data firstly elucidated that DNASE1L3 acts as a metastatic suppressor by attenuating E-cadherin ubiquitination degradation via the MYH9/β-catenin/c-Jun/LncRNA-KDM4A axis in NPC. DNASE1L3 is a potential marker for predicting NPC prognosis.
Tao et al. (Wed,) studied this question.