LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required forMCCgrowthin vitroandin vivo. We show thatLSD1 inhibition inMCCdisrupts theLSD1-CoRESTcomplex leading to displacement and degradation ofHMG20B (BRAF35), a poorly characterized complex member that is essential forMCCproliferation. Inhibition ofLSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance ofLSD1 for maintaining cellular plasticity and proliferation inMCC. There is also growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination ofLSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy forMCCpatients.