Similar Datasets
Project description:RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL.SignificanceMETTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller, p. 176. This article is highlighted in the In This Issue feature, p. 171.
| S-EPMC10150290 | biostudies-literature
Project description:RNA splicing dysregulation is a hallmark of cancers, promoting the onset and progression of disease. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ~20% of patients. However, the underlying mechanism for splicing defects in spliceosome unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover proteins involved in RNA splicing are post-transcriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing (factors) complexes is an independent risk factor and associated with poor prognosis in CLL. Moreover, increased splicing factor expression is highly correlated with METTL3, an RNA methyltransferase that modifies N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo, and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification mediated ribosome recycling and decoding process. Our results uncover a novel regulatory axis of METTL3 for splicing dysregulation in CLL and highlight m6A modification as a major contributor to spliceosome mutation-independent splicing defects that lead to CLL progression.
2023-03-03 | GSE223729 | GEO
Project description:RNA splicing dysregulation is a hallmark of cancers, promoting the onset and progression of disease. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ~20% of patients. However, the underlying mechanism for splicing defects in spliceosome unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover proteins involved in RNA splicing are post-transcriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing (factors) complexes is an independent risk factor and associated with poor prognosis in CLL. Moreover, increased splicing factor expression is highly correlated with METTL3, an RNA methyltransferase that modifies N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo, and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification mediated ribosome recycling and decoding process. Our results uncover a novel regulatory axis of METTL3 for splicing dysregulation in CLL and highlight m6A modification as a major contributor to spliceosome mutation-independent splicing defects that lead to CLL progression.
2023-03-03 | GSE223728 | GEO
Project description:RNA splicing dysregulation is a hallmark of cancers, promoting the onset and progression of disease. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ~20% of patients. However, the underlying mechanism for splicing defects in spliceosome unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover proteins involved in RNA splicing are post-transcriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing (factors) complexes is an independent risk factor and associated with poor prognosis in CLL. Moreover, increased splicing factor expression is highly correlated with METTL3, an RNA methyltransferase that modifies N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo, and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification mediated ribosome recycling and decoding process. Our results uncover a novel regulatory axis of METTL3 for splicing dysregulation in CLL and highlight m6A modification as a major contributor to spliceosome mutation-independent splicing defects that lead to CLL progression.
2023-03-03 | GSE223730 | GEO
Project description:METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression
| PRJNA927575 | ENA
Project description:METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [MeRIP-seq]
| PRJNA927821 | ENA
Project description:METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [Ribo-seq]
| PRJNA927820 | ENA
Project description:METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [RNA-seq]
| PRJNA927494 | ENA
Project description:Background: Osteosarcoma (OS) is the most prevalent bone cancer among children and adolescents, with relatively high mortality rates. RNA N6-methyladenosine (m6A) is the most common human mRNA modification with diverse functions in a variety of biological processes. Previous studies indicated that methyltransferase-like 3 (METTL3), the first methyltransferase to be identified, acted as an oncogene or tumor suppressor in multiple human cancers. However, its functions and underlying mechanisms in OS progression remain unclear; therefore, we explored these processes. Methods: We used real-time quantitative PCR (RT-qPCR) and Western blot assays to explore METTL3 expression in OS tumor tissues and five OS cell lines to assess its clinical significance. To further examine the functional role of METTL3 during OS progression, CCK-8 analyses, transwell assays, and xenograft model studies were conducted after silencing METTL3. Additionally, underlying mechanisms were also explored using RIP-seq and RIP-qPCR approaches. Results: METTL3 was upregulated in OS tumor tissues and cell lines and was associated with a worse prognosis. Moreover, METTL3 silencing suppressed OS cell proliferation, migration, and invasion. Also, in vivo METTL3 oncogenic functions were confirmed in the xenograft model. Comprehensive mechanistic analyses identified long non-coding RNA (lncRNA) DANCR as a potential target of METTL3, as indicated by reduced DANCR levels after METTL3 silencing. Also, lncRNA DANCR knockdown repressed OS cell proliferation, migration, and invasion. Furthermore, both METTL3 and lncRNA DANCR silencing significantly suppressed OS growth and metastasis. Finally, we hypothesized that METTL3 regulated DANCR expression via m6A modification-mediated DANCR mRNA stability. Conclusion: METTL3 contributes to OS progression by increasing DANCR mRNA stability via m6A modification, meaning that METTL3 may be a promising therapeutic target for OS treatment.
| S-EPMC8790117 | biostudies-literature
Project description:ObjectiveN6-methyladenosine (m6A) RNA methylation is involved in governing the mechanism of tumor progression. We aimed to excavate the biological role and mechanism of the m6A methyltransferase METTL3 in cholangiocarcinoma (CCA).MethodsMETTL3 expression was determined by database and tissue microarray analyses. The role of METTL3 in CCA was explored by loss- and gain-of-function experiments. The m6A target of METTL3 was detected by RNA sequencing. The role of AKR1B10 in CCA was explored, and the association between METTL3 and AKR1B10 was confirmed by rescue experiments.ResultMETTL3 expression was upregulated in CCA tissue, and higher METTL3 expression was implicated in poor prognoses in CCA patients. Overexpression of METTL3 facilitated proliferation, migration, invasion, glucose uptake, and lactate production in CCA cells, whereas knockdown of METTL3 had the opposite effects. We further found that METTL3 deficiency inhibited CCA tumor growth in vivo. RNA sequencing and MeRIP-qPCR confirmed that METTL3 enhanced AKR1B10 expression and m6A modification levels. Furthermore, METTL3 directly binds with AKR1B10 at an m6A modification site. A CCA tissue microarray showed that AKR1B10 expression was upregulated in CCA tissue and that silencing AKR1B10 suppressed the malignant phenotype mentioned above in CCA. Notably, knockdown of AKR1B10 rescued the tumor-promoting effects induced by METTL3 overexpression.ConclusionElevated METTL3 expression promotes tumor growth and glycolysis in CCA through m6A modification of AKR1B10, indicating that METTL3 is a potential target for blocking glycolysis for application in CCA therapy.
| S-EPMC9730622 | biostudies-literature