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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270976 | GEO | 2024/09/03

REPOSITORIES: GEO

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Project description:Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic mutations in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic mutations in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the underlying mechanisms of SEPSECS mutations, we generated a novel mouse model recapitulating the respective human pathogenic Y334C mutation in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, homozygous mutant pups died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by inactivating mutations of the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active site Sec to Cys in GPX4 surprisingly rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of Sepsecs-mutant mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with mutations in SEPSECS or GPX4 may benefit from treatments partially compensating for impaired GPX4 activity.

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

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