M6A-mediated ZNF750 repression facilitates nasopharyngeal carcinoma progression.
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ABSTRACT:
SUBMITTER: Zhang P
PROVIDER: S-EPMC6281568 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:An increasing number of studies have found that long non-coding RNA (lncRNA) play important roles in driving the progression of nasopharyngeal carcinoma (NPC). Our microarray screening revealed that expression of the lncRNA long intergenic non-protein coding RNA 173 (LINC00173) was upregulated in NPC. However, its role and mechanism in NPC have not yet been elucidated. In this study, we demonstrate that high LINC00173 expression indicated a poor prognosis in NPC patients. Knockdown of LINC00173 significantly inhibited NPC cell proliferation, migration and invasion in vitro. Mechanistically, LINC00173 interacted and colocalized with Ras-related protein Rab-1B (RAB1B) in the cytoplasm, but the modulation of LINC00173 expression did not affect the expression of RAB1B at either the mRNA or protein levels. Instead, relying on the stimulation of RAB1B, LINC00173 could facilitate the extracellular secretion of proliferation-associated 2G4 (PA2G4) and stromal cell-derived factor 4 (SDF4; also known as 45-kDa calcium-binding protein) proteins, and knockdown of these proteins could reverse the NPC aggressive phenotype induced by LINC00173 overexpression. Moreover, in vivo LINC00173-knockdown models exhibited a marked slowdown in tumor growth and a significant reduction in lymph node and lung metastases. In summary, LINC00173 serves as a crucial driver for NPC progression, and the LINC00173-RAB1B-PA2G4/SDF4 axis might provide a potential therapeutic target for NPC patients.
| S-EPMC9980309 | biostudies-literature
Project description:BackgroundDistant metastasis and recurrence remain the main obstacle to nasopharyngeal carcinoma (NPC) treatment. However, the molecular mechanisms underlying NPC growth and metastasis are poorly understood.MethodsLHX2 expression was examined in NPC cell lines and NPC tissues using quantitative reverse transcription-polymerase chain reaction, western blotting and Immunohistochemistry assay. NPC cells overexpressing or silencing LHX2 were used to perform CCK-8 assay, colony-formation assay, EdU assay, wound-healing and invasion assays in vitro. Xenograft tumour models and lung metastasis models were involved for the in vivo assays. The Gene Set Enrichment Analysis (GSEA), ELISA assay, western blot, chromatin immunoprecipitation (ChIP) assay and Luciferase reporter assay were applied for the downstream target mechanism investigation.ResultsLIM-homeodomain transcription factor 2 (LHX2) was upregulated in NPC tissues and cell lines. Elevated LHX2 was closely associated with poor survival in NPC patients. Ectopic LHX2 overexpression dramatically promoted the growth, migration and invasion of NPC cells both in vitro and in vivo. Mechanistically, LHX2 transcriptionally increased the fibroblast growth factor 1 (FGF1) expression, which in turn activated the phosphorylation of STAT3 (signal transducer and activator of transcription 3), ERK1/2 (extracellular regulated protein kinases 1/2) and AKT signalling pathways in an autocrine and paracrine manner, thereby promoting the growth and metastasis of NPC. Inhibition of FGF1 with siRNA or FGFR inhibitor blocked LHX2-induced nasopharyngeal carcinoma cell growth, migration and invasion.ConclusionsOur study identifies the LHX2-FGF1-FGFR axis plays a key role in NPC progression and provides a potential target for NPC therapy.
| S-EPMC9519904 | biostudies-literature
Project description:Increasing evidence demonstrated that long non-coding RNA growth-arrest-specific transcript 5 (GAS5) serves as a critical regulator in cancer development and progression. However, its function and mechanism in nasopharyngeal carcinoma (NPC) is still not well elucidated. In this study, we investigate the functional role as well as the molecular mechanism of GAS5 in NPC progression. Our results indicated that GAS5 expression was elevated in NPC tissues and cells. High GAS5 expression was correlated with poor prognosis of NPC patients. GAS5 knockdown suppressed proliferation, migration and invasion, and induced apoptosis in NPC cells. Moreover, GAS5 could epigenetically suppress PTEN expression via recruiting enhancer of zeste homolog 2 (EZH2). PTEN knockdown could reverse the inhibitory effect of GAS5 inhibition on NPC progression. Furthermore, GAS5 knockdown suppressed the tumor growth in vivo. In summary, knockdown of GAS5 repressed proliferation, migration and invasion, and promoted apoptosis in NPC through epigenetically silencing PTEN via recruiting EZH2.
| S-EPMC9072714 | biostudies-literature
Project description:Epitranscriptomic remodeling such as N6 -methyladenosine (m6 A) modification plays a critical role in tumor development. However, little is known about the underlying mechanisms connecting m6 A modification and nasopharyngeal carcinoma (NPC) progression. Here, CBX1 is identified, a histone methylation regulator, to be significantly upregulated with m6 A hypomethylation in metastatic NPC tissues. The m6 A-modified CBX1 mRNA transcript is recognized and destabilized by the m6 A reader YTHDF3. Furthermore, it is revealed that CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation. In addition to its oncogenic effect, CBX1 can facilitate immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. Clinically, CBX1 serves as an independent predictor for unfavorable prognosis in NPC patients. The results reveal a crosstalk between epitranscriptomic and epigenetic regulation in NPC progression, and shed light on the functions of CBX1 in tumorigenesis and immunomodulation, which may provide an appealing therapeutic target in NPC.
| S-EPMC9798977 | biostudies-literature
Project description:Hypoxia and related oxidative stress are closely related to the development and treatment of hepatocellular carcinoma (HCC). However, the mechanism mediated by hypoxia in HCC has not yet been elucidated. Here, we found multifunction scaffold protein p54nrb/NONO exerted pleiotropic effects to regulate hypoxia transcription signals, thereby enhancing the progression of liver cancer. Extensive analysis of clinical data demonstrated that NONO was significantly upregulated and represented as a poor prognostic indicator of HCC. The crucial role of NONO in driving angiogenesis and glycolysis, two well-known cancer phenotypes mediated by hypoxia, was examined in vitro an in vivo. Mechanistically, NONO interacted with and stabilized both HIF-1 and HIF-2 complexes thus activating the transcription of hypoxia-induced genes. Besides, NONO bound pre-mRNA and subsequent mRNA of these genes to facilitate them splicing and mRNA stability, respectively. Thus, NONO knockout seriously disrupted the expression of a cluster of HIF-1/2 targets and impeded hypoxia-enhanced progression in HCC. In conclusion, NONO functioned as a multipurpose scaffold that interacted with HIF-1/2 complex and their downstream transcripts to facilitate the expression of hypoxia-induced genes, allowing malignant proliferation, indicating that NONO might be a potential therapeutic target for HCC.
| S-EPMC8211563 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast China, and its metastasis remains an unresolved clinical problem. Ferroptosis, a type of nonapoptotic cell death, is a critical pathway in tumor metastasis. Berberine (BBR), a plant alkaloid, has been explored as a potential anti-NPC metastatic agent; however, the underlying mechanisms are unknown. Here, we showed that BBR exerted its anti-metastasis role by inhibiting system Xc-/GSH/GPX4 axis-driven ferroptosis. The present study demonstrated for the first time that BBR induced ferroptosis in NPC cells by increasing reactive oxygen species, lipid peroxidation and cellular Fe2+ and that the ferroptosis inhibitors Ferrostatin-1 and Deferoxamine mesylate rescued BBR-induced NPC cell death. Moreover, the ferroptotic characteristics of BBR-treated NPC cells were observed using transmission electron microscopy. Mechanistically, system Xc- (SLC7A11 and SLC3A2) and GSH levels were found to be suppressed after treatment with BBR. We demonstrated that the system Xc-/GSH/GPX4 axis was a critical mediator of BBR-induced ferroptosis. Furthermore, GPX4, a key inhibitor of lipid peroxidation, was greatly suppressed by BBR at both protein and mRNA levels. Molecular docking results showed a strong interaction between GPX4 and BBR. Notably, GPX4 overexpression reversed the effect of BBR-induced ferroptosis in NPC cells. Finally, BBR-mediated inhibition of NPC metastasis was validated in vivo using a mouse model. Taken together, our data suggest that BBR induced ferroptosis of NPC cells via suppressing the system Xc-/GSH/GPX4 axis, provides new insights into the mechanism of BBR anti-NPC metastasis.
| S-EPMC10777030 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most prevalent reversible modification in eukaryotic mRNA, and it plays a critical role in tumor progression. The purpose of this study was to investigate the function and regulatory mechanisms of the methyltransferase METTL3 in renal cell carcinoma (RCC). METTL3 expression was upregulated and predicted a poor prognosis in patients with advanced RCC. METTL3 facilitated the proliferation, migration, and invasion of RCC cells, depending on its methylase activity. METTL3 positively regulated the expression of PLOD2, and both genes were triggered under prolonged hypoxia. Mechanistically, hypoxia-induced the binding of HIF-1α to the METTL3 promoter, which enhanced its transcriptional activity. METTL3-mediated m6A modifications of PLOD2 mRNA at 3'UTR region, promoting the translation of PLOD2 protein. Furthermore, silencing METTL3 impaired RCC progression in vitro. In vivo, administration of highly potent and selective METTL3 inhibitor STM2457 showed anti-tumor effects, whereas AAV9-mediated re-transduction of PLOD2 largely abolished the above phenomenon in a subcutaneous mouse model. These findings reveal that hypoxia and HIF-driven METTL3 transcription promote RCC progression by increasing PLOD2 expression in an m6A-dependent manner, suggesting that METTL3 may serve as a novel pharmaceutical intervention for RCC.
| S-EPMC10794171 | biostudies-literature
Project description:BackgroundColorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored.MethodsWestern blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3.ResultsUsing TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific m6A "reader", insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including "writer", "reader", and "target", exhibited a better prognostic value for CRC patients than any of these components individually.ConclusionsOverall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC.
| S-EPMC6589893 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic RNAs. Although the important roles of m6A in RNA fate have been revealed, the potential contribution of m6A to RNA function in various diseases, including hepatocellular carcinoma (HCC), is still unclear. In this study, we identified a novel m6A-modified RNA AC026356.1. We found that AC026356.1 was increased in HCC tissues and cell lines. High expression of AC026356.1 was correlated with poor survival of HCC patients. m6A modification level of AC026356.1 was also increased in HCC and more significantly correlated with poor survival of HCC patients. Functional assays showed that m6A-modified AC026356.1 promoted HCC cellular proliferation, migration, and liver metastasis. Gene set enrichment analysis showed that AC026356.1 activated IL11/STAT3 signaling. Mechanistic investigation showed that m6A-modified AC026356.1 bound to IGF2BP1. The interaction between m6A-modified AC026356.1 and IGF2BP1 promoted the binding of IL11 mRNA to IGF2BP1, leading to increased IL11 mRNA stability and IL11 secretion. Functional rescue assays showed that depletion of IL11 reversed the oncogenic roles of AC026356.1. These findings revealed the potential influences of m6A modification on RNA biological functions and suggested that targeting m6A modification may be a novel strategy for HCC treatment.
| S-EPMC10625930 | biostudies-literature
Project description:BackgroundAccumulating evidence shows that lncRNAs are widely involved cellular processes of various tumors. The aim of this study was to explore the potential role and molecular mechanism of lncRNA SNHG16 in nasopharyngeal carcinoma (NPC).MethodsSNHG16, miR-520a-3p, and MAPK1 levels were measured by RT-qPCR assay. CCK-8, colony formation, transwell, and flow cytometry assays were adopted to analyze the proliferation, migration, invasion, and apoptosis of NPC cell lines (SUNE1 and 5-8F). Murine xenograft model was used to investigate tumor growth and metastasis in vivo. Immunohistochemical staining was employed to evaluate the levels of Bcl-2, cleaved caspase-3, Bax, and Ki-67. Dual-luciferase reporter assays were conducted to analyze the binding ability between miR-520a-3p and SNHG16 or MAPK1.ResultsSNHG16 was overexpressed in NPC tissues and cells. High SNHG16 expression indicated a poor prognosis. SNHG16 knockdown could cause significant inhibition on cell proliferation and metastasis, induce cell apoptosis in NPC cells, and repressed tumor growth and metastasis in vivo. Additionally, SNHG16 could directly bind to miR-520a-3p, thus positively regulating MAPK1 expression. Moreover, functional analysis indicated that miR-520a-3p exerted a tumor-suppressing role in NPC progression. Rescue assays demonstrated that MAPK1 upregulation could abrogate the inhibitory effects on NPC cell proliferation and metastasis, as well as the promoting effects on NPC cell apoptosis caused by SNHG16 knockdown. In conclusion, SNHG16 contributed to the proliferation and metastasis of NPC cells by modulating the miR-520a-3p/MAPK1 axis.ConclusionThese results suggest that SNHG16 acts as an oncogene in the progression of NPC via modulating the miR-520a-3p/MAPK1 axis.
| S-EPMC8147710 | biostudies-literature