Integrative multiomics evaluation reveals the importance of pseudouridine synthases in hepatocellular carcinoma

Jin, Zhipeng; Ming, Song; Wang, Jianping; Zhu, Wenjing; Sun, Dongxu; Liu, Huayuan; Shi, Guangjun

doi:10.3389/fgene.2022.944681

“…Consistent with differential activity among pseudouridine synthases, chemotherapeutic resistance to 5-FU is often associated with increased expression of one of more pseudouridine synthases (Jin et al 2022). In hepatocellular carcinoma and colorectal cancer, higher expression of pseudouridine synthases (PUS1, PUS7, PusL1, RPUSD3, DKC1, PUS7L, PUS10, and RPUSD1) correlates with poor prognosis (Jin et al 2022; Liang et al 2022; Zhang et al 2023).…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with differential activity among pseudouridine synthases, chemotherapeutic resistance to 5-FU is often associated with increased expression of one of more pseudouridine synthases (Jin et al 2022). In hepatocellular carcinoma and colorectal cancer, higher expression of pseudouridine synthases (PUS1, PUS7, PusL1, RPUSD3, DKC1, PUS7L, PUS10, and RPUSD1) correlates with poor prognosis (Jin et al 2022; Liang et al 2022; Zhang et al 2023). Likewise, overexpression of the Dyskerin pseudouridine synthase that acts on rRNA (DKC1) predicts poor prognosis in breast cancer, while knockdown of DKC1 and Mek1/2 restricts colorectal cancer cell growth (Elsharawy et al 2020; Kan et al 2021).…”

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil Treatment Represses Pseudouridine-Containing Small RNA Export into Extracellular Vesicles

Qu,

Nelson,

Liu

et al. 2024

Preprint

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5-fluorouracil (5-FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5-FU is also incorporated into RNA causing toxicity due to defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. Here, we examine the impact of 5-FU on the expression and export of small RNAs (sRNAs) into small extracellular vesicles (sEVs). Moreover, we assess the role of 5-FU in regulation of post-transcriptional sRNA modifications (PTxM) using mass spectrometry approaches. EVs are secreted by all cells and contain a variety of proteins and RNAs that can function in cell-cell communication. PTxMs on cellular and extracellular sRNAs provide yet another layer of gene regulation. We found that treatment of the colorectal cancer (CRC) cell line DLD-1 with 5-FU led to surprising differential export of miRNA snRNA, and snoRNA transcripts. Strikingly, 5-FU treatment significantly decreased the levels of pseudouridine on both cellular and secreted EV sRNAs. In contrast, 5-FU exposure led to increased levels of cellular sRNAs containing a variety of methyl-modified bases. Our results suggest that 5-FU exposure leads to altered expression, base modifications, and mislocalization of EV base-modified sRNAs.

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“…According to the above results, we concluded that PUS1 may be a underlying diagnostic and prognostic gene for HCC, which was consistent with the result of Shi’ study. 23 We also explored the clinical application of PUS1 by joint-effect analysis, and the result manifested that patients with high PUS1 expression had a poorer prognosis when had another risk factor.…”

Section: Discussionmentioning

confidence: 99%

“… 21 , 22 Moreover, a study showed that some PUS enzymes play a diagnostic and prognostic role for HCC. 23 …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PUS1 May Be a Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma

Lan¹,

Huang²,

Liao³

et al. 2023

PGPM

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Objective The mechanisms of pseudouridine synthase (PUS) are not definite in hepatocellular carcinoma (HCC), the objective of this study is to investigate the effect of PUS genes in HCC. Materials and Methods Differentially expressed and prognostic gene of PUS enzymes was identified based on The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. For the identified gene, pseudouridine synthase 1 ( PUS1 ), was used for further research. The clinicopathological feature of PUS1 was analyzed by Student’s t -test. Prognostic significance was explored by Kaplan-Meier (KM) analysis and Cox proportional hazards regression model. Receiver operating characteristic (ROC) curve was applied to appraise diagnostic and prognostic value. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Gene Set Enrichment Analysis (GSEA) were implemented to explore mechanism of PUS1 . A Guangxi cohort was applied to verify differential expression. In vitro cell experiments were implemented to investigate the influence for proliferation, reactive oxygen species (ROS) level, migration, and invasion of HCC cells after a knockdown of PUS1 . Results PUS1 was significantly overexpressed in HCC tissues, and patients with high PUS1 were related to unpromising clinicopathological features. Survival analysis revealed high PUS1 expression was associated with a poor overall survival (OS) and 1 year-recurrence free survival (RFS), was an independent risk factor. Meanwhile, ROC curve showed that PUS1 had a diagnostic and prognostic significance to HCC. Functional enrichment analysis implied that PUS1 may be involved in metabolic pathways, mitochondrial function, non-alcoholic fatty liver disease (NAFLD), and some important carcinogenic pathways. Cell assays revealed that knockdown of PUS1 significantly constrained the migration, proliferation, invasion and improved the ROS level of HCC cells. Conclusion PUS1 may be a prognostic biomarker and a underlying treatment target for HCC.

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5‐Fluorouracil treatment represses pseudouridine‐containing miRNA export into extracellular vesicles

Qu,

Nelson,

Liu

et al. 2024

J of Extracellular Bio

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Abstract5‐Fluorouracil (5‐FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5‐FU is also incorporated into RNA causing defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. We examined the impact of 5‐FU on post‐transcriptional small RNA modifications (PTxMs) and the expression and export of RNA into small extracellular vesicles (sEVs). EVs are secreted by all cells and contain a variety of proteins and RNAs that can function in cell‐cell communication. We found that treatment of colorectal cancer (CRC) cells with 5‐FU represses sEV export of miRNA and snRNA‐derived RNAs, but promotes export of snoRNA‐derived RNAs. Strikingly, 5‐FU treatment significantly decreased the levels of pseudouridine on both cellular and sEV small RNA profiles. In contrast, 5‐FU exposure led to increased levels of cellular small RNAs containing a variety of methyl‐modified bases. These unexpected findings show that 5‐FU exposure leads to altered RNA expression, base modification, and aberrant trafficking and localization of small RNAs.

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Integrative multiomics evaluation reveals the importance of pseudouridine synthases in hepatocellular carcinoma

Cited by 19 publications

References 56 publications

5-Fluorouracil Treatment Represses Pseudouridine-Containing Small RNA Export into Extracellular Vesicles

5-Fluorouracil Treatment Represses Pseudouridine-Containing Small RNA Export into Extracellular Vesicles

PUS1 May Be a Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma

5‐Fluorouracil treatment represses pseudouridine‐containing miRNA export into extracellular vesicles

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