RNA sequencing: new technologies and applications in cancer research

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: Dec. 1, 2020

Abstract Over the past few decades, RNA sequencing has significantly progressed, becoming a paramount approach for transcriptome profiling. The revolution from bulk to single-molecular, single-cell and spatial approaches enabled increasingly accurate, individual cell resolution incorporated with information. Cancer, major malignant heterogeneous lethal disease, remains an enormous challenge in medical research clinical treatment. As vital tool, been utilized many aspects of cancer therapy, including biomarker discovery characterization heterogeneity evolution, drug resistance, immune microenvironment immunotherapy, neoantigens so on. In this review, latest studies on technology their applications are summarized, future challenges opportunities discussed.

Language: Английский

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N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: July 27, 2021

Abstract N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects fates of modified RNAs, including their stability, splicing, and/or translation, thus plays important roles posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute deposition on distinct RNAs by own or forming different complexes additional partner proteins. In this review, we summarize function these regulating key genes pathways cancer biology. We also highlight progress use mediating therapy resistance, chemotherapy, targeted therapy, immunotherapy radiotherapy. Finally, discuss current approaches clinical potential methyltransferase-targeting strategies.

Language: Английский

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The roles and implications of RNA m6A modification in cancer

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(8), P. 507 - 526

Published: May 23, 2023

Language: Английский

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Role of m6A writers, erasers and readers in cancer

Experimental Hematology and Oncology, Journal Year: 2022, Volume and Issue: 11(1)

Published: Aug. 9, 2022

Abstract The N(6)-methyladenosine (m6A) modification is the most pervasive of human RNAs. In recent years, an increasing number studies have suggested that m6A likely plays important roles in cancers. Many demonstrated involved biological functions cancer cells, such as proliferation, invasion, metastasis, and drug resistance. addition, closely related to prognosis patients. this review, we highlight advances understanding function various We emphasize importance progression look forward describe future research directions.

Language: Английский

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m⁶A modification of lncRNA PCAT6 promotes bone metastasis in prostate cancer through IGF2BP2‐mediated IGF1R mRNA stabilization

Clinical and Translational Medicine, Journal Year: 2021, Volume and Issue: 11(6)

Published: June 1, 2021

Abstract Background Bone metastasis is the leading cause of tumor‐related death in prostate cancer (PCa) patients. Long noncoding RNAs (lncRNAs) have been well documented to be involved progression multiple cancers. Nevertheless, role lncRNAs PCa bone remains largely unclear. Methods The expression cancer‐associated transcripts was analyzed published datasets and further verified clinical samples cell lines by RT‐qPCR situ hybridization assays. Colony formation assay, MTT cycle analysis, EdU Transwell migration invasion assays, wound healing vivo experiments were carried out investigate function transcript 6 ( PCAT6 ) tumor growth PCa. Bioinformatic RNA pull‐down, RIP assays conducted identify proteins binding potential targets . therapeutic targeting antisense oligonucleotides (ASO) explored Results upregulated tissues with increased predicted poor prognosis Functional found that knockdown significantly inhibited invasion, migration, proliferation vitro , as Mechanistically, METTL3 ‐mediated m A modification contributed upregulation an IGF2BP2 ‐dependent manner. Furthermore, IGF1R enhancing mRNA stability through / RNA‐protein three‐dimensional complex. Importantly, inhibition ASO showed against Finally, correlation demonstrated cells. Conclusions Our study uncovers a novel molecular mechanism which A‐induced axis promotes growth, suggesting may serve promising prognostic marker target bone‐metastatic

Language: Английский

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METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

Cancer Cell International, Journal Year: 2022, Volume and Issue: 22(1)

Published: Jan. 7, 2022

Abstract Background N6-methyladenosine (m 6 A) has emerged as a significant regulator of the progress various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored biological function and underlying mechanism methyltransferase-like 3 (METTL3), main catalyst m A, LUAD progression. Methods The expression METTL3, YTHDF1 SLC7A11 were detected by immunochemistry or/and online datasets patients. effects METTL3 on cell proliferation, apoptosis ferroptosis assessed through vitro loss-and gain-of-function experiments. vivo effect tumorigenesis was evaluated using xenograft mouse model. MeRIP-seq, RNA immunoprecipitation stability assay conducted to explore molecular LUAD. Results results showed that A level, well methylase both significantly elevated patients cancer cells. Functionally, found could promote proliferation inhibit different models, while knockdown suppressed growth cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), subunit system Xc − , identified direct target mRNA-seq MeRIP-seq. METTL3-mediated modification stabilize mRNA translation, thus promoting inhibiting ferroptosis, novel form programmed death. Additionally, demonstrated YTHDF1, reader, recruited enhance modification. Moreover, positively correlated with tissues. Conclusions These findings reinforced oncogenic progression revealed correlation ferroptosis; these also indicate is promising diagnosis therapy.

Language: Английский

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METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner

Oncogene, Journal Year: 2022, Volume and Issue: 41(11), P. 1622 - 1633

Published: Jan. 29, 2022

Abstract N6-methyladenosine (m 6 A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore biological function and clinical significance m A methyltransferase METTL3 intrahepatic cholangiocarcinoma (ICC). In this study, we revealed that upregulated predicted poor prognosis patients with ICC. Multivariate regression analysis demonstrated expression an independent predictor for overall survival Moreover, knockdown inhibited ICC progression, while overexpression showed opposite effect. inhibitor STM2457 also anti-tumor effect Mechanistically, transcription driven by H3K4me3 activation. Upregulation mediated modification IFIT2 mRNA accelerated decay a YTHDF2-dependent manner, which promoted development lead poorer prognosis. summary, our findings activation-driven METTL 3 promotes progression YTHDF2-mediated degradation, suggesting may serve as potential target human therapy.

Language: Английский

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Genetic and epigenetic defects of the RNA modification machinery in cancer

Trends in Genetics, Journal Year: 2022, Volume and Issue: 39(1), P. 74 - 88

Published: Nov. 12, 2022

Cancer was initially considered to be an exclusively genetic disease, but interplay of dysregulated and epigenetic mechanisms is now known contribute the cancer phenotype. More recently, chemical modifications RNA molecules - so-called epitranscriptome have been found regulate various aspects function homeostasis. Specific enzymes, as RNA-modifying proteins (RMPs), are responsible for depositing, removing, reading in RNA. Intensive investigations epitranscriptomic field recent years, conjunction with great technological advances, revealed critical role regulating numerous cellular pathways. Furthermore, growing evidence has that modification machinery often altered human cancers, highlighting enormous potential RMPs pharmacological targets or diagnostic markers.

Language: Английский

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Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3

Cancer Research, Journal Year: 2022, Volume and Issue: 82(13), P. 2444 - 2457

Published: May 4, 2022

Abstract N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A various aspects of cancer biology. In this study, we aimed to explore the biological tumor metastasis and identify novel therapeutic strategies esophageal squamous cell carcinoma (ESCC). Integration genome-wide CRISPR/Cas9 functional screening with highly invasive metastatic ESCC subline models led identification METTL3, catalytic subunit N6-adenosine-methyltransferase complex, as promoter metastasis. METTL3 expression was upregulated tumors tissues. vitro vivo experiments indicated that increased EGR1 mRNA enhanced its stability YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into regulation found KAT2A H3K27 acetylation levels region activated transcription whereas SIRT2 exerted opposite effects. Molecular docking computational Food Drug Administration–approved compound library consisting 1,443 small molecules identified compounds targeting suppress Elvitegravir, originally developed treat human immunodeficiency virus (HIV) infection, suppressed by directly enhancing STUB1-mediated proteasomal degradation. Overall, modifications are important metastasis, elvitegravir has potential treating ESCC. Significance: This study finds promotes signaling m6A-dependent revealing vulnerability blockade carcinoma.

Language: Английский

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ALKBH5 regulates STAT3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6A-YTHDF2-dependent manner

EBioMedicine, Journal Year: 2022, Volume and Issue: 80, P. 104019 - 104019

Published: April 28, 2022

N6-methyladenosine (m6A) is the most common and abundant mRNA modification it plays crucial roles in many biological processes. However, as a key RNA demethylase, alkylation repair homolog protein 5 (ALKBH5) has not been well studied human osteosarcoma. The present study sought to explore ALKBH5-mediated m6A underlying mechanisms osteosarcoma.The expression of ALKBH5 its correlation with clinicopathological features were examined by bioinformatics analysis tissue microarrays. Cellular proliferation was detected CCK8 assays. Cell cycle apoptosis analyzed TUNEL Flow cytometry assay. Finally, investigation regulatory mechanism osteosarcoma performed MeRIP assay, RNA-sequencing, dual luciferase reporter pull-down stability Tumor xenograft models established for vivo experiments.Our data showed that low associated worse overall survival patients. Reducing levels cells through up-regulation lead cell inhibition, arrest. We identified SOCS3, negative regulator STAT3, downstream target modification. And modified SOCS3 recognized YTHDF2, which promotes decay SOCS3. Mechanistically, our revealed inactivated STAT3 pathway increasing via an m6A-YTHDF2-dependent manner.M6A methylation rising affecting tumorigenicity tumor progression. Our findings illuminate clinical significance growth, suggesting potential biomarker treatment osteosarcoma.This work supported Science Technology foundation Hubei, China (Grant No.2017CFB762); Tongji hospital No.2201103013); National Natural Foudation (No.82002849).

Language: Английский

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