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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKIs remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations; however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures (PARIS) method is used to establish the higher-order RNA structure maps of EGFR-TKIs-resistant and -sensitive cells of NSCLC. Our results show that RNA structural regions are enriched in untranslated regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N6-threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs. RNA structure formation in YRDC 3′ UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.

Lenvatinib is the latest and promising agent that has demonstrated a significant improvement of progression-free survival in advanced hepatocellular carcinoma (HCC). However, resistance emerges soon after initial treatment, limiting the clinical benefits of lenvatinib. Therefore, understanding the mechanism of resistance is necessary for improving lenvatinib efficacy. YRDC promotes the proliferation of hepatocarcinoma cells via regulating the activity of the RAS/RAF/MEK/ERK pathway, which was the primary pathway of the anticancer effect of lenvatinib. The purpose of this study is to investigate whether YRDC modulates the sensitivity of lenvatinib in hepatocarcinoma cells. Using the CCK-8 cell viability assay, wound-healing assay and clone formation assay in cell models, and xenograft assay in null mouse, we demonstrated that Huh7 cells with YRDC knockdown showed decreased susceptibility to lenvatinib than their control cells. Furthermore, we found that lenvatinib inhibited the expression of YRDC in a time-dependent manner. This effect may aggravate resistance to lenvatinib in hepatocarcinoma cells and may be an underlying cause of resistance, which emerges soon after lenvatinib initial treatment. To investigate how YRDC modulates the sensitivity of lenvatinib, we assessed the effect of tRNA with different t6A levels on the translation of the KRAS gene by in vitro rabbit reticulocyte translation system and measured the expression levels of the KRAS gene by western blot together with qPCR. We found that YRDC regulates the protein translation of KRAS in cell models, and the tRNA with low t6A modification level reduces the translation of the KRAS in the in vitro translation system. These results suggested that YRDC mediates the resistance of lenvatinib in hepatocarcinoma cells via modulating the translation of the KRAS. In this study, YRDC was confirmed to be a potential novel predictive biomarker of lenvatinib sensitivity in HCC. [ABSTRACT FROM AUTHOR]

Lenvatinib is the latest and promising agent that has demonstrated a significant improvement of progression-free survival in advanced hepatocellular carcinoma (HCC). However, resistance emerges soon after initial treatment, limiting the clinical benefits of lenvatinib. Therefore, understanding the mechanism of resistance is necessary for improving lenvatinib efficacy. YRDC promotes the proliferation of hepatocarcinoma cells via regulating the activity of the RAS/RAF/MEK/ERK pathway, which was the primary pathway of the anticancer effect of lenvatinib. The purpose of this study is to investigate whether YRDC modulates the sensitivity of lenvatinib in hepatocarcinoma cells. Using the CCK-8 cell viability assay, wound-healing assay and clone formation assay in cell models, and xenograft assay in null mouse, we demonstrated that Huh7 cells with YRDC knockdown showed decreased susceptibility to lenvatinib than their control cells. Furthermore, we found that lenvatinib inhibited the expression of YRDC in a time-dependent manner. This effect may aggravate resistance to lenvatinib in hepatocarcinoma cells and may be an underlying cause of resistance, which emerges soon after lenvatinib initial treatment. To investigate how YRDC modulates the sensitivity of lenvatinib, we assessed the effect of tRNA with different t6A levels on the translation of the KRAS gene by in vitro rabbit reticulocyte translation system and measured the expression levels of the KRAS gene by western blot together with qPCR. We found that YRDC regulates the protein translation of KRAS in cell models, and the tRNA with low t6A modification level reduces the translation of the KRAS in the in vitro translation system. These results suggested that YRDC mediates the resistance of lenvatinib in hepatocarcinoma cells via modulating the translation of the KRAS. In this study, YRDC was confirmed to be a potential novel predictive biomarker of lenvatinib sensitivity in HCC.

Accumulating evidence suggested that YrdC involved in growth, telomere homeostasis, translation and the N6-threonylcarbamoylation (t6A) of tRNA was abnormally expressed in the progression of tumor. However, the role of YrdC in hepatocellular carcinoma remained elusive. Our study aimed to investigate the clinical significance and oncogenic phenotypes of YrdC in hepatocellular carcinoma, and to determine its related mechanism of this disease. With the usage of GEO datasets, we analyzed the expression of YrdC in hepatocellular carcinoma (HCC). Kaplan-Meier survival analysis was used to evaluate the prognostic significance of hepatocellular carcinoma patients in TCGA. Gain- and loss-of-function analyses in vitro of YrdC were also performed to evaluate its effects on oncogenic phenotypes and relevant signaling pathways. YrdC expression was not only dysregulated in hepatocellular carcinoma tissue but also related to the prognosis of patients with hepatocellular carcinoma. In addition, YrdC depletion suppressed the capability of proliferation, migration and invasion of huh7 cells, while there was opposite result for YrdC overexpression. Our data also unraveled that YrdC promoted the progression of HCC by activating MEK/ERK signaling pathways. Together, our findings indicated that YrdC was a potential prognosis marker for hepatocellular carcinoma, and therapeutic strategies targeting YrdC might hold promise in improving the treatment of hepatocellular carcinoma.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKIs remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations; however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures (PARIS) method is used to establish the higher-order RNA structure maps of EGFR-TKIs-resistant and -sensitive cells of NSCLC. Our results show that RNA structural regions are enriched in untranslated regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N 6 -threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs. RNA structure formation in YRDC 3' UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The yrdC family of genes codes for proteins that occur both independently and as a domain in proteins that have been implicated in regulation. An example for the latter case is the sua5 gene from yeast. Sua5 was identified as a suppressor of a translation initiation defect in cytochrome c and is required for normal growth in yeast (Na JG, Pinto I, Hampsey M, 1992, Genetics 11:791-801). However, the function of the Sua5 protein remains unknown; Sua5 could act either at the transcriptional or the posttranscriptional levels to compensate for an aberrant translation start codon in the cyc gene. To potentially learn more about the function of YrdC and proteins featuring this domain, the crystal structure of the YrdC protein from Escherichia coli was determined at a resolution of 2.0 Å. YrdC adopts a new fold with no obvious similarity to those of other proteins with known three-dimensional (3D) structure. The protein features a large concave surface on one side that exhibits a positive electrostatic potential. The dimensions of this depression, its curvature, and the fact that conserved basic amino acids are located at its floor suggest that YrdC may be a nucleic acid binding protein. An investigation of YrdC's binding affinities for single- and double-stranded RNA and DNA fragments as well as tRNAs demonstrates that YrdC binds preferentially to double-stranded RNA. Our work provides evidence that 3D structures of functionally uncharacterized gene products with unique sequences can yield novel folds and functional insights. [ABSTRACT FROM AUTHOR]

• YrdC expression was dysregulated in hepatocellular carcinoma tissues and related to the poor prognosis. • YrdC promotes hepatocellular carcinoma cell proliferation, migration and invasion. • YrdC promotes tumor growth in vivo. • YrdC contributed to the proliferation and metastasis of HCC cells, probably by activating of MEK/ERK signaling pathway. Accumulating evidence suggested that YrdC involved in growth, telomere homeostasis, translation and the N6-threonylcarbamoylation (t6A) of tRNA was abnormally expressed in the progression of tumor. However, the role of YrdC in hepatocellular carcinoma remained elusive. Our study aimed to investigate the clinical significance and oncogenic phenotypes of YrdC in hepatocellular carcinoma, and to determine its related mechanism of this disease. With the usage of GEO datasets, we analyzed the expression of YrdC in hepatocellular carcinoma (HCC). Kaplan-Meier survival analysis was used to evaluate the prognostic significance of hepatocellular carcinoma patients in TCGA. Gain- and loss-of-function analyses in vitro of YrdC were also performed to evaluate its effects on oncogenic phenotypes and relevant signaling pathways. YrdC expression was not only dysregulated in hepatocellular carcinoma tissue but also related to the prognosis of patients with hepatocellular carcinoma. In addition, YrdC depletion suppressed the capability of proliferation, migration and invasion of huh7 cells, while there was opposite result for YrdC overexpression. Our data also unraveled that YrdC promoted the progression of HCC by activating MEK/ERK signaling pathways. Together, our findings indicated that YrdC was a potential prognosis marker for hepatocellular carcinoma, and therapeutic strategies targeting YrdC might hold promise in improving the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggested that microRNA (miRNA) plays important regulatory roles in the initiation and development of various cancers. Previous study showed that microRNA-206 (miR-206) is dysregulated in human bladder cancer tissues, however, the biological function and underlying mechanisms of miR-206 in human bladder cancer remain unknown. In the present study, we aimed to investigate the clinical significance of miR-206 and its target gene YRDC in human bladder cancer, and to determine its effects on oncogenic phenotypes of this disease. Our results showed that miR-206 expression was downregulated significantly in bladder cancer tissues and cell lines compared with adjacent normal bladder tissues and human bladder epithelial immortalized SV-HUC-1 cell line, respectively. Overexpression of miR-206 reduced the expression of YRDC and inhibited bladder cancer cell proliferation, colony formation, migration, invasion and induced cell cycle arrest at G0/G1 phase. In addition, knockdown of YRDC exhibited similar effects with miR-206 overexpression in bladder cancer cells and restoration of YRDC partially reversed the effects of miR-206 in bladder cancer cells. These findings indicated that mir-206 might be a novel target for bladder cancer therapy by targeting YRDC.