Cancer is a global health issue that impairs the life quality of patients and origins thousands of deaths annually worldwide. Six-transmembrane epithelial antigen of the prostate (STEAP1) was identified to be overexpressed in several types of cancers, namely in prostate cancer (PCa). Considering its secondary structure, associated with its location in the cell membrane, has been suggested a role in intercellular communication between tumour cells. Taking into account its high specificity and overexpression in human cancers, STEAP1 is nowadays a promising candidate to be imposed as a therapeutic target. Several strategies have been developed during the last few years for targeting STEAP1, including antibody-drug conjugates, monoclonal antibodies (mAbs), DNA vaccines and small noncoding RNAs (ncRNAs). This review presents the current knowledge about STEAP1 protein expression in human tissues, its biochemical properties and targeting strategies with the purpose to evaluate its potential as therapeutic agent for cancer.

Protein synthesis rate and accuracy are essential for bona fide protein synthesis and proteome homeostasis (proteostasis), however the mRNA translation elongation factors that prevent protein mistranslation, misfolding and aggregation are poorly understood. To address this question, we evaluated the role of 70 yeast tRNA modifying enzyme genes on protein aggregation and used mass spectrometry to identify the aggregated and mistranslated proteins. We show that the mitochondrial tRNA-modifying enzyme Slm3 thiolates the cytoplasmic tRNAs at position 34 and that decreased levels of mcm 5 s 2 U34 in SLM3 mutants are compensated by increasing mcm 5 U34, ncm 5 U34 and ncm 5 Um34 levels. In the tRNA gene knockout strains, stress response proteins are overrepresented in protein aggregates and their genes are enriched in codons decoded by tRNAs lacking mcm 5 U34, mcm 5 s 2 U34, ncm 5 U34, ncm 5 Um34, modifications. Increased rates of amino acid misincorporation were detected in the yeast ELP1, SLM3 and TRM9 gene knockout mutants at protein sites that specifically mapped to the codons sites that are decoded by the hypomodified tRNAs, demonstrating that U34 tRNA modifications safeguard the proteome from translational errors, misfolding and cellular proteotoxic stress..

Protein synthesis rate and accuracy are essential for bona fide protein synthesis and proteome homeostasis (proteostasis), however the mRNA translation elongation factors that prevent protein mistranslation, misfolding and aggregation are poorly understood. To address this question, we evaluated the role of 70 yeast tRNA modifying enzyme genes on protein aggregation and used mass spectrometry to identify the aggregated and mistranslated proteins. We show that the mitochondrial tRNA-modifying enzyme Slm3 thiolates the cytoplasmic tRNAs at position 34 and that decreased levels of mcm5s2U34 in SLM3 mutants are compensated by increasing mcm5U34, ncm5U34 and ncm5Um34 levels. In the tRNA gene knockout strains, stress response proteins are overrepresented in protein aggregates and their genes are enriched in codons decoded by tRNAs lacking mcm5U34, mcm5s2U34, ncm5U34, ncm5Um34, modifications. Increased rates of amino acid misincorporation were detected in the yeast ELP1, SLM3 and TRM9 gene knockout mutants at protein sites that specifically mapped to the codons sites that are decoded by the hypomodified tRNAs, demonstrating that U34 tRNA modifications safeguard the proteome from translational errors, misfolding and cellular proteotoxic stress.

Transfer RNAs (tRNAs) are widely known for their roles in the decoding of the linear mRNA information into amino acid sequences of proteins. They are also multifunctional platforms in the translation process and have other roles beyond translation, including sensing amino acid abundance, interacting with the general stress response machinery, and modulating cellular adaptation, survival, and death. In this mini-review, we focus on the emerging role of tRNA genes in the organization and modification of the genomic architecture of yeast and the role of tRNA misexpression and decoding infidelity in genome stability, evolution, and adaption. We discuss published work showing how quickly tRNA genes can mutate to meet novel translational demands, how tRNAs speed up genome evolution, and how tRNA genes can be sites of genomic instability. We highlight recent works showing that loss of tRNA decoding fidelity and small alterations in tRNA expression have unexpected and profound impacts on genome stability. By dissecting these recent evidence, we hope to lay the groundwork that prompts future investigations on the mechanistic interplay between tRNAs and genome modification that likely triggers genome evolution.

The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in several human tumors, particularly in prostate cancer (PCa). However, the mechanisms involved in its overexpression remain unknown. It is well known that epigenetic modifications may result in abnormal gene expression patterns, contributing to tumor initiation and progression. Therefore, this study aimed to analyze the methylation pattern of the STEAP1 gene in PCa versus non-neoplastic cells. Bisulfite amplicon sequencing of the CpG island at the STEAP1 gene promoter showed a higher methylation level in non-neoplastic PNT1A prostate cells than in human PCa samples. Bioinformatic analysis of the GEO datasets also showed the STEAP1 gene promoter as being demethylated in human PCa, and a negative association with STEAP1 mRNA expression was observed. These results are supported by the treatment of non-neoplastic PNT1A cells with DNMT and HDAC inhibitors, which induced a significant increase in STEAP1 mRNA expression. In addition, the involvement of HDAC in the regulation of STEAP1 mRNA expression was corroborated by a negative association between STEAP1 mRNA expression and HDAC4,5,7 and 9 in human PCa. In conclusion, our work indicates that STEAP1 overexpression in PCa can be driven by the hypomethylation of STEAP1 gene promoter.