Interfering with aggregated a-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins

Melanoma is the most serious and deadly form of skin cancer and with progression to advanced melanoma, the intrinsically disordered protein a-synuclein is upregulated to high levels; and while toxic to dopaminergic neurons in Parkinson's disease, it is highly beneficial for primary and metastatic melanoma cells. To gain detailed insights, both at the level of the proteome and the transcriptome, into this exact opposite role of a-synuclein in advanced melanoma, we performed proteomic studies of high-level a-synuclein-expressing primary and metastatic human melanoma cell lines and proteomic and transcriptomic studies of metastatic human melanoma xenografts treated systemically with the diphenyl-pyrazole small-molecule compound anle138b, which binds to and interferes with the oligomeric structure of a-synuclein. The results of these studies reveal that interfering with oligomerized a-synuclein in these tumor xenografts led to a substantial upregulation of expression of major histocompatibility complex proteins in the melanoma cells, the latter of which is pertinent to enhancing anti-melanoma immune responses. Overall design: RNA-seq analysis of WM983-B human melanoma tumor xenografts treated systemically with the diphenyl-pyrazole small-molecule compound anle138b, which binds to and interferes with the oligomeric structure of a-synuclein