Molecular Mechanisms Underlying the Metastasis Suppressor Activity of NME1 in Malignant Melanoma

Abstract

Metastatic melanoma is exceedingly lethal and is responsible for the majority of skin cancer related deaths. Impactful research on melanoma metastasis is crucial to improving prognosis. The discovery of metastasis suppressor genes, genes that inhibit metastasis but do not affect tumor growth, have advanced the field of metastasis research. NME1 (also referred to as NDPK-A or NM23-H1) was the first identified metastasis suppressor gene. NME1 is a multifaceted molecule, executing numerous cellular functions which are attributable to the suppressor phenotype. Our lab previously identified a signature of NME1-regualted genes which have prognostic value in human melanoma. As such, we hypothesize that NME1 possess an understudied transcriptional activity to regulate one or more of these signature genes. In the present study, we identified Aldolase C (ALDOC) from the gene signature as an ideal candidate to assess NME1 transcriptional activity. NME1 induced mRNA and protein expression of ALDOC in multiple melanoma cell lines. Transcriptional regulation was evidenced by elevated expression of ALDOC pre-mRNA and activation of the ALDOC promoter in NME1-expressing melanoma cells. Employing chromatin immunoprecipitation, we demonstrated NME1 localizes to the ALDOC gene and enriches the presence of active transcription indicators at the ALDOC promoter. Together, we provide novel systematic evidence for NME1 transcriptional activity, which may further be explored as a mechanism for the metastasis suppressor function. Furthermore, we establish unequivocal metastasis suppressor capability of NME1 using a transgenic mouse model susceptible to developing melanoma upon exposure to ultraviolet (UV) radiation. Mice deficient in NME1 expression experienced significantly increased melanoma metastases to the lung and lymph nodes compared to wild-type mice. Taken together, our studies demonstrate NME1 as a robust metastasis suppressor of UV-induced melanoma, and provide evidence for novel transcription factor activity of NME1. We aim to enhance our understanding of melanoma metastasis through our continued research of the metastasis suppressor gene, NME1.