Targeting lysine-specific demethylase 1 inhibits melanoma metastasis via the NF2-Hippo-YAP pathway

Melanoma, originating from the malignant change in skin melanocytes, is highly metastatic, yet effective treatments to prevent its spread are still lacking. Lysine-specific histone demethylase 1 (LSD1) functions as an epigenetic modifier; however, its role in melanoma remains incompletely elucidated. In this study, we determined that LSD1 expression is upregulated in metastatic melanoma relative to primary melanoma, which is indicative of a poor prognosis. Subsequent experiments revealed that targeting LSD1 effectively suppresses melanoma metastasis in both in vitro and in vivo models. Mechanistically, the pharmacological or genetic inhibition of LSD1 induces the phosphorylation and subsequent degradation of Yes-associated protein (YAP), a critical component of the Hippo signaling pathway that is strongly linked to tumor metastasis. Furthermore, ChIP-qPCR analysis indicates that the LSD1 inhibition enhances H3K4me2 modification at the promoter regions of NF2 and LATS1/2, thereby promoting their transcriptional activation. This results in increased expression of NF2 (encoded by NF2) and LATS1/2, ultimately activating the Hippo pathway. These findings not only enhance our understanding of the molecular mechanisms driving melanoma metastasis but also establish a novel theoretical basis for the development of LSD1 inhibitors and targeted therapeutic strategies for melanoma.