Tumor suppressor genes are frequently targeted by mutations introducing premature termination codons (PTC) in the protein coding sequence, both in sporadic cancers and in the germline of patients with cancer predisposition syndromes. These mutations have a high pathogenic impact since they generate C-terminal truncated proteins with altered stability and function. In addition, PTC mutations trigger transcript degradation by nonsense-mediated mRNA decay. Suppression of PTC by translational readthrough restores protein biosynthesis and stabilizes the PTC-targeted mRNA, making a suitable therapeutic approach the reconstitution of active full-length tumor suppressor proteins by pharmacologically-induced translational readthrough. Here, we review the recent advances in small molecule pharmacological induction of translational readthrough of disease-associated PTC from tumor suppressor genes, and discuss the therapeutic potential of translational readthrough in specific groups of patients with hereditary syndromic cancers.

Bladder cancer (BCa) is a highly invasive tumor with few successful therapies, and its unfavorable prognosis mainly stems from late diagnosis and resistance to treatment. Ferroptosis is a type of non-apoptotic cell death characterized by iron-dependent regulated necrosis due to extensive lipid peroxidation. Glycolysis is fundamental to cancer cell metabolism, with cancer cells developing various strategies to enhance this process. In this study, we combined ferroptosis and glycolysis gene sets, two biological processes closely related to tumorigenesis and development, and obtained ferroptosis and glycolysis-related gene sets (FGRGs). By leveraging both single-cell and bulk transcriptome data from BCa, we have investigated the presence and role of FGRGs in the onset and progression of BCa through various approaches. Using machine learning algorithms, we identified a feature gene set consisting of 13 genes in the TCGA data set to predict the prognosis of BCa and verified it in the GEO data set. After that, we explored FGRGs in depth using a variety of bioinformatics analyses, such as mutational landscape analysis, functional enrichment analysis, immune infiltration analysis, FGRGs-associated risk and clinical characterization, and drug susceptibility analysis. Finally, we validated the function of the core gene chondroitin polymerizing factor 2 (CHPF2) using CCK-8, clone formation, transwell, and wound healing assays. Our research innovatively combines ferroptosis with glycolytic genes and applies it as an independent prognostic factor in the study of BCa. It reveals new characteristic genes and therapeutic targets that can predict the prognosis of BCa patients and lays a foundation for the study of the occurrence and development mechanism of BCa and targeted data strategies.

Numerous kidney functions exhibit substantial circadian oscillations, such as renal blood flow, glomerular filtration rate, tubular reabsorption function, and erythropoietin production. The onset and the injury of acute kidney injury caused by ischemia or drugs also have a circadian rhythmicity. Contrast media are widely used in clinical diagnosis and treatment; however, whether contrast-induced kidney injury exhibits a time-of-day dependence is unknown. We retrospectively analyzed 33 patients who underwent percutaneous coronary angiography and found that contrast induced the increase of serum neutrophil gelatinase-associated lipocalin (NGAL) was more obvious in the group who underwent operation during 6:00 ~ 13:00 than the group who underwent operation between 13:00 ~ 20:00. In addition, C57BL/6J mice were injected with iohexol at different times. The kidney injury of mice injected with iohexol at ZT12 was more severe than that at ZT0, which was manifested in the increase of urinary KIM1 and NGAL, enhanced renal tubular lipid peroxidation, and increased tubular ferroptosis. Inhibition of ferroptosis could alleviate kidney injury induced by iohexol at ZT12. Mechanistically, we found that nuclear factor erythrocyte 2-associated factor 2 (NRF2) expression has a 24-h circadian rhythm and is directly regulated by CLOCK. Administration of 4-Octyl itaconate at ZT12 to increase NRF2 expression could attenuate iohexol-induced tubular ferroptosis. These findings provide a new insight into the pathology of contrast medium-induced kidney injury, in which oscillatory NRF2 expression regulated by CLOCK contributes to the susceptibility of contrast-induced kidney injury in a time-of-day-specific fashion.

Proline- and serine-rich coiled-coil 1 (PSRC1) has been implicated in various cancers, yet its role in breast cancer (BRCA) remains incompletely understood. Here, we employed the UALCAN database to explore PSRC1 expression in BRCA and obtained survival prognosis data from the Kaplan-Meier Plotter database. Additionally, PSRC1 expression was analyzed in 81 pairs of BRCA tissues and their corresponding adjacent noncancerous tissues through quantitative real-time PCR, western blotting, and immunohistochemistry. We observed PSRC1 was overexpressed in BRCA tissues, especially in triple negative breast cancer (TNBC). Higher PSRC1 levels correlated with poorer outcomes for BRCA patients. In 81 BRCA tumor tissues, PSRC1 protein levels were significantly associated with positive vessel tumor embolus. Subsequently, the clinical relevance of PSRC1 in BRCA was assessed using the chi-square test, the Kaplan-Meier model with a Log-rank test, as well as univariate and multivariate analyses. Patients with high PSRC1 had worse prognoses. Elevated PSRC1 expression served as an independent predictor of prognosis. Moreover, we investigated the effects of PSRC1 on BRCA cell phenotypes in MCF-7 and BT549 cells and used a mouse xenograft model with BT549 cells to determine its invivo effect. Both invitro and invivo experiments demonstrated that silencing PSRC1 inhibited cell proliferation, migration, and tumor development. In summary, our results indicate that high PSRC1 expression is closely linked to BRCA patient survival and could be a valuable prognostic biomarker for this disease.

IUBMB Life is the flagship journal of the International Union of Biochemistry and Molecular Biology and is devoted to the rapid publication of the most novel and significant short articles, reviews and papers in the broadly defined fields of biochemistry, molecular biology, cell biology, and molecular medicine.

Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia‐inducible factors (HIFs) HIF‐1α, HIF‐2α, and HIF‐3α. However, in contrast to HIF‐1α and HIF‐2α, a specific role for HIF‐3α in cancer biology has not yet been clearly established. This research was aimed to elucidate the role of HIF‐3α in colon cancer. As reported previously for HIF‐1α and HIF‐2α, we found that HIF‐3α is also overexpressed under normoxic conditions in all cancer cell lines examined and in patient‐derived tumor tissue samples compared with non‐malignant cells and normal tissue, but remarkably, pulse‐chase experiments demonstrated that HIF‐3α displays high stability in cells compared with HIF‐1α and HIF‐2α. Progno Scan data analysis showed that overexpression of HIF‐3α correlated with a patient's lower survival rate and a poor prognosis in colon adenocarcinoma patients. Knockdown of HIF‐3α expression was carried out to investigate the effects derived from its silencing on malignant phenotype. We found a significative decrease in the Hypoxia Response Element (HRE) reporter transcriptional activity mediated by HIF‐3α and a reduction in cell viability under oxidative stress in colon cancer cells with HIF‐3α knockdown compared with control HIF‐3α expressing cells. In addition, HIF‐3α silencing also produced an increase in apoptotic rate, decreased clonogenic capacity, altered autophagy flux, and modulated the canonical Wnt/β pathway in an isoform‐dependent and cell context‐dependent manner in colon cancer cells. Overall, these data show that transcriptional activity mediated by HI3‐3α plays an essential role in promoting the malignant phenotype, cell survival, and resistance to cell death in CRC cells.

The role of RGPR-p117, a transcription factor, which binds to the TTGGC motif in the promoter region of the regucalcin gene, in cell regulation remains to be investigated. This study elucidated whether RGPR-p117 regulates the activity of triple-negative human breast cancer MDA-MB-231 cells in vitro. The wild-type and RGPR-p117-overexpressing cancer cells were cultured in DMEM supplemented with fetal bovine serum. RGPR-p117 overexpression suppressed colony formation and growth of cancer cells. Stimulatory effects of epidermal growth factor on cell growth were blocked by RGPR-p117 overexpression. Wild-type cell proliferation was repressed by cell cycle and intracellular signaling inhibitors. These effects were not potentiated in transfectants. Overexpressed RGPR-p117 protected cancer cells against apoptosis inducers. Mechanistic results showed that RGPR-p117 overexpression decreased the expression of Ras, PI3-kinase, Akt, mitogen-activated protein kinase, and mTOR, which are involved in cell growth, while it elevated the levels of the cancer cell suppressor p53, Rb, p21, and regucalcin. Overexpression of RGPR-p117 suppressed cancer cell migration and adhesion. Interestingly, osteoblastic MC3T3-E1 cells or macrophage RAW264.7 cells involved in the bone microenvironment were impaired by coculture with MDA-MB-231 cells. The effects of cancer cells were blocked by transfection. Coculture with conditioned medium obtained from breast cancer cells repressed proliferation and enhanced the death of osteoblastic cells and macrophages. A TNF-α signaling inhibitor blocked these effects. Thus, overexpressed RGPR-p117 was found to suppress the activity of breast cancer cells by regulating various signaling processes, providing new insight into cellular signaling regulation.

IUBMB Life is the flagship journal of the International Union of Biochemistry and Molecular Biology and is devoted to the rapid publication of the most novel and significant short articles, reviews and papers in the broadly defined fields of biochemistry, molecular biology, cell biology, and molecular medicine.

F. Virgili , F. Acconcia , R. Ambra , A. Rinna , P. Totta , and M. Marino , "Nutritional Flavonoids Modulate Estrogen Receptor α Signaling," IUBMB Life 56, no. 3 (2004): 145-151, https://doi.org/10.1080/15216540410001685083. The above article, published online on 3 January 2008 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Efstathios S. Gonos; the International Union of Biochemistry and Molecular Biology; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Specifically, duplication of several Western Blot bands has been detected within Figure 2a. The relative raw data could no longer be accessed due to the considerable time elapsed since the article's publication. The corresponding author, Maria Marino, maintains that the concerns do not impact the overall results and conclusions of the study, and disagrees with the decision of retraction. However, the article is retracted as the editors have lost trust in the integrity of the data presented and consider the conclusions invalid.

Heterozygous pathogenic variants in the histidyl‐tRNA synthetase (HARS) gene are associated with Charcot–Marie–Tooth (CMT) type 2W disease, classified as an axonal peripheral neuropathy. To date, at least 60 variants causing CMT symptoms have been identified in seven different aminoacyl‐tRNA synthetases, with eight being found in the catalytic domain of HARS. The genetic data clearly show a causative role of aminoacyl‐tRNA synthetases in CMT; however, the cellular mechanisms leading to pathology can vary widely and are unknown in the case of most identified variants. Here we describe a novel HARS variant, c.412T>C; p.Y138H, identified through a CMT gene panel in a patient with peripheral neuropathy. To determine the effect of p.Y138H we employed a humanized HARS yeast model and recombinant protein biochemistry, which identified a deficiency in protein dimerization and a growth defect which shows mild but significant improvement with histidine supplementation. This raises the potential for a clinical trial of histidine.