DNPH1 exerts context-dependent tumor-promoting and -repressing functions during melanoma development

Metastatic cutaneous melanoma is a highly lethal and multifarious disease that is driven by the interplay between UV-induced DNA damage and oncogenic lesions, yet enzymes coupling these processes remain incompletely defined. We uncovered the deoxynucleotide hydrolase DNPH1 as an overexpressed melanoma enzyme associated with metastasis and poorer patient survival. DNPH1 overexpression or downregulation in human melanoma cells enhanced or lowered, respectively, their in vitro growth rate. In vivo, Dnph1 loss delayed melanoma initiation and reduced distant metastasis in UV light-exposed, BRAF-V600E-expressing mice. Similarly, Dnph1 knockout in conjunction with oncogenic BRAF-V600E slowed melanoma onset upon ablation of the tumor suppressor TP53. Surprisingly, Dnph1 knockout facilitated growth of tumors after their establishment, indicating stage-specific functions during melanoma development. Mechanistically, UV light triggered the translocation of DNPH1 into the cell nucleus, where it may alter DNA repair pathway choice by suppressing nucleotide excision repair while enhancing homologous recombination and non-homologous end joining. DNPH1 also promoted NF-κB signaling, which may involve cooperation with two interaction partners, ANXA2 and FHL2, in stimulating NF-κB-dependent transcription. Altogether, these findings have identified DNPH1 as a previously unrecognized regulator in the development of cutaneous melanomas where it functions in a context-dependent manner as a tumor promoter or attenuator.