DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway

Summary: Background: Distant metastasis remains the leading cause of treatment failure in patients with nasopharyngeal carcinoma (NPC), making it critical to identify efficient therapeutic targets for metastatic NPC. Previous studies have demonstrated that deoxynucleotidyltransferase terminal-interacting protein 1 (DNTTIP1) is associated with the development of various types of cancer. However, its role and mechanism in NPC have not been explored. Methods: RNA-seq profiling was performed for three pairs of NPC and normal nasopharynx tissues. DNTTIP1 expression in NPC specimens was detected by immunohistochemistry. In vitro and in vivo assays were used to investigate the function of DNTTIP1. The molecular mechanism was determined using RT-qPCR, western blotting, RNA-seq, luciferase reporter assays, ChIP assays, and co-IP assays. Findings: DNTTIP1 was found to be significantly upregulated in NPC tissues. Furthermore, DNTTIP1 promoted NPC growth and metastasis in vitro and in vivo. Upregulation of DNTTIP1 in NPC indicated poor clinical outcomes. Mechanistically, DNTTIP1 suppressed DUSP2 gene expression via recruiting HDAC1 to its promoter and maintaining a deacetylated state of histone H3K27. The downregulation of DUSP2 resulted in aberrant activation of the ERK signaling and elevated MMP2 levels, promoting NPC metastasis. Chidamide, an HDAC inhibitor, was shown to suppress NPC metastasis by regulating the DNTTIP1/HDAC1-DUSP2 axis. Interpretation: Our findings demonstrate that DNTTIP1 not only regulates NPC metastasis but also independently predicts NPC prognosis. Furthermore, targeting DNTTIP1/HDAC1 by Chidamide may benefit NPC patients with metastasis. Funding: This work was supported by the National Natural Science Foundation of China (No. 81872464, 82073243).