Targeting SP1 for ubiquitination and degradation: a novel antimelanoma mechanism of dihydroartemisinin

Melanoma is one of the deadliest tumor types, with a low survival rate due to a high recurrence rate, fast metastatic spread, and drug resistance. Therefore, it is urgent to discover new therapeutic targets and develop novel drugs that improve the clinical efficacy. Although dihydroartemisinin (DHA) suppresses melanoma cell proliferation and migration, the mechanism as to how it functions remains elusive. Here, RNA sequencing discovers that DHA upregulates 790 genes and downregulates 2342 genes in melanoma cells, with cadherin-3 ( CDH3 ) among the most significantly downregulated genes. CDH3 expression augments while its knockdown attenuates melanoma cell proliferation. Intriguingly, DHA facilitates the ubiquitination and proteasomal degradation of the CDH3 transcription factor specificity protein 1 (SP1) by enhancing its interaction with Kelch-like ECH-associated protein 1 (KEAP1), the substrate receptor of an E3 ubiquitin ligase, thereby inhibiting the CDH3/PI3K/AKT/GSK3β/β-catenin signaling pathway. Finally, we demonstrate that SP1 expression rescues melanoma cells from the inhibitory effect of DHA in a xenograft mouse model. Collectively, this work elucidates an unrecognized mechanism by which DHA suppresses melanoma cell proliferation and migration by acting as a molecular glue and promoting the ubiquitination and proteasomal degradation of SP1. This discovery will shed new insights into the mechanisms of action of DHA and its potential in translation research.