Abstract
SAMMSON is expressed in the majority of human melanomas and promotes cell growth and survival.
Major finding: SAMMSON is expressed in the majority of human melanomas and promotes cell growth and survival.
Mechanism: SAMMSON binds to p32, promoting p32-mediated mitochondrial functions and melanoma cell survival.
Impact: SAMMSON inhibition may effectively target melanoma cells and sensitize them to MAPK inhibition.
Focal amplifications of chromosome 3p13-3p14 in a subset of melanomas are associated with a poor prognosis. The melanoma specific oncogene MITF is located within this amplicon; however, the possible contribution of other loci to the development of melanoma has not been determined. Using data from The Cancer Genome Atlas, Leucci and colleagues discovered that chromosome 3p amplifications in melanoma encompass the SAMMSON long noncoding RNA (lncRNA) and although MITF and SAMMSON were coamplified in about 10% of melanomas, SAMMSON and MITF levels were not generally correlated. Further, SAMMSON was expressed in the majority of malignant melanomas but was barely detectable in normal melanocytes and benign lesions, suggesting that it is induced as cells become fully transformed, and is a candidate biomarker of malignant melanoma. Putative SOX binding sites were present upstream of SAMMSON, and SOX10 knockdown reduced SAMMSON expression, indicating that SAMMSON is a SOX10 target gene. SAMMSON silencing reduced melanoma cell growth and survival independent of the transcriptional state of BRAF, NRAS, or TP53, and cells that are intrinsically resistant to BRAF inhibition were sensitive to SAMMSON silencing. Further, SAMMSON silencing enhanced the effects of BRAF and MEK inhibitors, and cells with acquired resistance to BRAF inhibition remained sensitive to SAMMSON targeting. SAMMSON was shown to bind directly to the mitochondrial metabolism protein p32, and promoted its mitochondrial localization and function. SAMMSON silencing phenocopied the effects of p32 silencing, causing functional and structural defects including fewer and fragmented cristae, and reduced density of the mitochondrial matrix, suggesting that SAMMSON silencing kills melanoma cells in part through disruption of p32-mediated mitochondrial functions. Inhibition of SAMMSON in patient-derived melanoma xenografts was well tolerated, reduced tumor proliferation, enhanced apoptosis, and potentiated the effects of BRAF inhibition. Together these results indicate that SAMMSON may be an informative biomarker of melanoma malignancy, and SAMMSON inhibition may reduce melanoma cell growth and survival.
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