Preventing melanomagenesis through modulating HMGB1 palmitoylation

Melanoma is most aggressive and malignant form of skin cancer, the incidence of which has increased significantly over the past decades. Thus, a better understanding of how melanoma arises from pre-malignant lesions is critical for cancer prevention. Ultraviolet (UV) exposure has been identified as a major factor associated with melanoma initiation. Strong UV irradiation could lead to DNA-damage and cell death of keratinocytes, and the release of HMGB1, which promotes inflammation, angiogenesis, and tumorigenesis by directly modulating melanoma and anti-tumor immune microenvironment. HMGB1 is both nuclear and extracellular protein, involved in DNA replication, repair and pro-tumorigenic inflammation, respectively. We have found that HMGB1 is posttranslationally palmitoylated at conserved Cys106 residue. HMGB1 undergoes “autopalmitoylation” when binds to palmitoyl-CoA independent of palmitoyltransferases. Palmitoylation of HMGB1 promotes its nuclear localization and chromatin binding. Loss of palmitoylation promotes its cytoplasmic localization and secretion. In addition, fatty acids inhibit HMGB1 secretion in keratinocytes after UV-damage. Interestingly, we found that silencing of HMGB1 in melanoma cells suppresses their proliferation, and we identified an alkylating compound, inhibiting HMGB1 palmitoylation and melanoma growth. Our findings linked fatty acids, protein palmitoylation to pro-tumorigenic microenvironment in skin, and have profound impact in understanding the mechanisms of UV-mediated melanomagenesis and providing potential therapeutic options for melanoma. This work is funded in part by Melanoma Research Alliance (MRA) postdoctoral fellowship (812717 to Z. T). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.