selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis [Xenograft Human]

Oxidative stress has been shown to limit metastasis of numerous cancer types including melanoma. A specialized group of 25 proteins containing the 21st amino acid, selenocysteine, plays a central role in oxidative stress resistance, which is a key driver of metastasis. A single selenocysteine tRNA methylation, Um34, is required for the translation of several stress-related selenoproteins in a selenium-dependent manner. Herein, we characterize FTSJ1 as the Um34 methyltransferase and show that its activity is required for the Sec tRNA (tRNASec) Um34 modification. Loss of Um34 affects translation of a subset of selenoproteins and increases melanoma cell sensitivity to oxidative stress while increased Um34 levels promote oxidative stress resistance. Loss of FTSJ1 does not affect primary melanoma tumor growth but abolishes metastatic spread in vivo. Overexpression of FTSJ1 specifically increases melanoma metastasis in vivo. Our work establishes FTSJ1 as the Um34 methyltransfearse and tRNASec Um34 modification as a central regulator of oxidative stress resistance during melanoma metastasis. Overall design: Patient-derived melanoma cells were injected subcutaneously into NSG mice. Liver metastases and primary tumor samples were collected at endpoint and ribosome profiling was completed to investigate changes in selenoprotein translation during metastasis