The role of DNPH1 (a deoxynucleotide hydrolase) in melanoma development, examining its effects on tumor initiation, growth, and metastasis using human melanoma cell lines and UV-exposed, BRAF-V600E-expressing mouse models, including TP53-ablated conditions.
DNPH1 overexpression increased and knockdown decreased in vitro melanoma cell growth; in vivo, Dnph1 loss delayed melanoma initiation and reduced distant metastasis, but paradoxically accelerated tumor growth after establishment — indicating stage-specific, context-dependent tumor-promoting and tumor-repressing functions. Mechanistically, UV light triggered DNPH1 nuclear translocation, where it suppressed nucleotide excision repair while enhancing HR and NHEJ, and promoted NF-κB signaling via interaction with ANXA2 and FHL2.
Mechanistic findings are largely based on in vitro cell studies and mouse models, which may not fully recapitulate human melanoma biology; the precise molecular mechanism linking DNPH1 nuclear translocation to DNA repair pathway switching is not fully resolved; and the study does not assess DNPH1 inhibition as a therapeutic strategy in clinical or preclinical treatment settings.
DNPH1 overexpression is associated with metastasis and poorer survival in melanoma patients, making it a potential biomarker, but its dual role as both a tumor promoter (at initiation) and attenuator (post-establishment) means that therapeutic targeting of DNPH1 would need to be carefully timed and context-specific.
