Ferroptosis, an iron-dependent non-apoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here we reported that the RNA binding protein RBMS1 participated in lung cancer development through mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 was a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3¢-and 5¢-UTRs of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake and promotes ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis.Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potentials and clinical values.
Sexual maturation and somatic growth cessation are associated with adolescent development, which is precisely controlled by interconnected neuroendocrine regulatory pathways in the endogenous endocrine system. The pituitary gland is one of the key regulators of the endocrine system. By analyzing the RNA sequencing (RNA-seq) transcriptome before and after sexual maturation, in this study, we characterized the global gene expression patterns in zebrafish pituitaries at 45 and 90 days post-fertilization (dpf). A total of 15 043 annotated genes were expressed in the pituitary tissue, 3072 of which were differentially expressed with a greater than or equal to twofold change between pituitaries at 45 and 90 dpf. In the pituitary transcriptome, the most abundant transcript was gh. The expression levels of gh remained high even after sexual maturation at 90 dpf. Among the eight major pituitary hormone genes, lhb was the only gene that exhibited a significant change in its expression levels between 45 and 90 dpf. Significant changes in the pituitary transcripts included genes involved in the regulation of immune responses, bone metabolism, and hormone secretion processes during the juvenile-sexual maturity transition. Real-time quantitative PCR analysis was carried out to verify the RNA-seq transcriptome results and demonstrated that the expression patterns of the eight major pituitary hormone genes did not exhibit a significant gender difference at 90 dpf. For the first time, we report the quantitative global gene expression patterns at the juvenile and sexual maturity stages. These expression patterns may account for the dynamic neuroendocrine regulation observed in body metabolism.
Stem-loop binding protein (SLBP) is required for replication-dependent histone mRNA metabolism in mammals. Zebrafish possesses two , and is necessary for retinal neurogenesis. However, the detailed expression and function of in zebrafish are still unknown. In this study, we first identified zebrafish as an oocyte-specific maternal factor and then generated a maternal-zygotic F3 homozygous mutant (MZΔ4) using CRISPR/Cas9. The depletion of maternal Slbp2 disrupted early nuclear cleavage, which resulted in developmental arrest at the MBT stage. The developmental defects could be rescued in transgenic MZΔ4 embryos. However, homozygous mutant MZΔ1 developed normally, indicating is dispensable for zebrafish early embryogenesis. Through comparative proteome and transcriptome profiling between WT and MZΔ4 embryos, we identified many differentially expressed proteins and genes. In comparison with those in WT embryos, four replication-dependent histones, including H2a, H2b, H3, and H4, all reduced their expression, while histone variant significantly increased in MZΔ4 embryos at the 256-cell stage and high stage. Zebrafish Slbp2 can bind histone mRNA stem-loop in vitro, and the defects of MZΔ4 embryos can be partially rescued by overexpression of H2b. The current data indicate that maternal Slbp2 plays a pivotal role in the storage of replication-dependent histone mRNAs and proteins during zebrafish oogenesis.
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