Acetaldehyde metabolism by ALDH2 induces melanocyte activation, transformation, and melanoma initiation

Summary: Abstract Body: Despite public health campaigns advocating sun protection, melanoma incidence continues to rise in the U.S., prompting reconsideration of other risk factors. Acetaldehyde (AcAH), a genotoxic metabolite of ethanol (EtOH), is classified as a human carcinogen. We previously demonstrated that aldehyde dehydrogenase 2 (ALDH2), a key enzyme in AcAH metabolism, influences melanoma incidence and prognosis. However, the precise links between ALDH2, EtOH/AcAH exposure, and melanoma development remain unclear. In this study, we used human melanocytes and genetically engineered mice to determine the effects of EtOH and its metabolite, AcAH. We found that melanocytes were significantly less effective at eliminating AcAH than keratinocytes and hepatocytes due to lower ALDH2 activity despite their transiently induced ALDH2 activity upon EtOH exposure. When melanocytes were exposed to EtOH with an ALDH2 inhibitor, they showed enhanced PKA signaling and adenylyl cyclase activity, produced more melanin, extended dendrites, and proliferated. Metabolomic analysis revealed alterations in glycolysis and TCA cycle and elevated oncometabolite levels, along with activation of a one-carbon cycle, in human melanocytes treated with EtOH and ALDH2 inhibitor, suggesting increased DNA methylation and mutagenesis. DNA analysis showed CPD formation and mutations in BRAF, NRAS, CDKN2A, and TP53 in human melanocytes treated with EtOH and the ALDH2 inhibitor. Finally, we cross-bred mouse lines to generate offspring hemizygous for Tg(Tyr-cre/ERT2)13Bos, heterozygous for Braftm1Mmcm, and homozygous for Aldh2tm1kaw. When administered tamoxifen to activate the oncogenic driver and treated with EtOH, these mice developed cutaneous melanoma on the trunk and tails within 2 months, whereas water-ingested mice or other genotypes did not develop melanoma. Our findings underscore the critical role of AcAH (i.e., EtOH in the context of ALDH2 inhibition) in melanocyte activation, transformation, and melanoma initiation. Takeshi Yamauchi¹, Zili Zhai¹, Kimtrang Nguyen¹, Charlotte Kwong¹, Mayumi Fujita¹ 1. Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States. Pigmentation, Melanoma, and Melanoma Immune Surveillance