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PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [RNA-seq]

ABSTRACT: Epigenetic modifications play important roles during the pathogenesis of multiple myeloma (MM). Here, we found that protein arginine methyltransferase 1 (PRMT1) was highly expressed in MM patients and its expression level was positively correlated with MM stages. High PRMT1 expression were notably related to adverse prognosis in MM patients. We further showed that silencing PRMT1 inhibited MM proliferation and tumorigenesis in vitro and in vivo. Mechanistically, we revealed that knockdown of PRMT1 reduced the oxidative phosphorylation (OXPHOS) of MM cells through downregulation of NDUFS6. Meanwhile, we identified that WTAP, a key component of the m6A methyltransferase complex, was methylated by PRMT1 and NDUFS6 was identified as a bona fide m6A target of WTAP. Finally, we found that PRMT1 inhibitor and bortezomib combination synergistically inhibited MM progression. Collectively, our results demonstrate that PRMT1 plays a crucial role during MM tumorigenesis and suggest that PRMT1 could be a potential therapeutic target in MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235403 | GEO | 2023/11/09

REPOSITORIES: GEO

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PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [m6A-Seq]

Project description:Epigenetic modifications play important roles during the pathogenesis of multiple myeloma (MM). Here, we found that protein arginine methyltransferase 1 (PRMT1) was highly expressed in MM patients and its expression level was positively correlated with MM stages. High PRMT1 expression were notably related to adverse prognosis in MM patients. We further showed that silencing PRMT1 inhibited MM proliferation and tumorigenesis in vitro and in vivo. Mechanistically, we revealed that knockdown of PRMT1 reduced the oxidative phosphorylation (OXPHOS) of MM cells through downregulation of NDUFS6. Meanwhile, we identified that WTAP, a key component of the m6A methyltransferase complex, was methylated by PRMT1 and NDUFS6 was identified as a bona fide m6A target of WTAP. Finally, we found that PRMT1 inhibitor and bortezomib combination synergistically inhibited MM progression. Collectively, our results demonstrate that PRMT1 plays a crucial role during MM tumorigenesis and suggest that PRMT1 could be a potential therapeutic target in MM.

2023-11-10 | GSE235404 | GEO

Profiling of N6-methyladenosine in HepG2 cells: SETD2, METTL3, METTL14 or WTAP knockdown and control cells

Project description:SETD2 is the specific methyltransferase of H3K36me3, while METTL3, METTL14 and WTAP are the components of m6A methyltransferase complex. To understand the global effect of H3K36me3 on m6A modification, we compared the m6A profiling in SETD2 and METTL3, METTL14 or WTAP knockdown HepG2 cells, and found depletion of H3K36me3 by SETD2 silencing globally reduced m6A in human transcriptome. What’s more, most of the SETD2-dependent hypomethylation sites also responded to knockdown of METTL3, METTL14, or WTAP.

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WTAP-mediated m6A modification profiling in human nasopharyngeal carcinoma cell lines

Project description:N(6)-methyladenosine (m6A) plays an important role in the tumorigenesis and progression of cancers. However, the clinical significance of m6A and their regulatory mechanisms in nasopharyngeal carcinogenesis (NPC) remain largely unknown. In this study, we used the microarray analysis to study WTAP-mediated m6A modification profiles in human nasopharyngeal carcinoma cell line, HONE-1, by comparing 3 pairs of samples with or without WTAP knockdown.

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PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [m6A-Seq]

Project description:PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [m6A-Seq]

| PRJNA985996 | ENA

PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6

Project description:PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6

| PRJNA985994 | ENA

PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [RNA-seq]

Project description:PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [RNA-seq]

| PRJNA985995 | ENA

LC-MS/MS analysis of co-immunoprecipitation products of METTL3

Project description:N6-methyladenosine (m6A) methylation of mRNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the mechanism of MTC assembly remains elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3), that is highly expressed in breast cancer. Furthermore, we find that both METTL3a and full-length METTL3 are required for MTC assembly, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is required for METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC assembly. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A methylation, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Consequently, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component for MTC assembly, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

2023-08-18 | PXD036899 | Pride

TTC22 increasing total m6A RNA level and colon cancer metastasis via RPL4-WTAP-YTHDF1 axis

Project description:WTAP is an essential component of the RNA N-6-methyladenosine (m6A) modification complexes that guides METLL3-METLL14 heteroduplexes to target RNAs in the nucleus of mammalian cells. Through mining the genotype-tissue expression (GTEx) datasets, we initially found that TTC22 expression was highly correlated with WTAP and FTO in many normal human tissues. Our experimental results indicate that TTC22 could directly capture RNA binding protein RPL4, induce the binding between RPL4 and WTAP mRNA in the cytoplasm, which increased the m6A level, induced alterative splicing, enhanced the stability and translation efficiency of WTAP mRNA, and consequently upregulated the level of total m6A RNA. These results indicate that WTAP mRNA is a m6A target and there is a positive feedback loop between total m6A and WTAP expression. YTHDF1 was found to be an essential m6A WTAP mRNA binding protein. Downregulation of RPL4, WTAP, or YTHDF1 expression could reverse TTC22-enhanced total m6A RNA level. m6A-specific antibody immunoprecipitated RNA-sequencing (meRIP-seq) demonstrated that TTC22 caused dramatic expression changes of genes related to metabolic pathways, ribosome biogenesis, and RNA spliceosome. Furthermore, we also found that TTC22 upregulated the expression of epithelial-mesenchymal transition (EMT)-related gene SNAI1 via m6A, and promoted metastasis of colon cancer in vitro and in mice. In conclusion, our study illustrates that WTAP mRNA is a m6A target using YTHDF1 as the binding protein. TTC22 could upregulate the levels of WTAP expression and total m6A RNA through the PRL4 binding. The m6A-mediated upregulation of SNAI1 expression may contribute to TTC22-enhanced colon cancer metastasis.

2024-11-10 | GSE188521 | GEO

PRMT1 controls the Senescence Associated Secretory Phenotype in Replication Stress Response

Project description:The protein arginine methyltransferase PRMT1 is overexpressed in various human cancers and linked to poor response to therapy. Although various inhibitors targeting its activity are under development, we still do not fully understand how PRMT1 is involved in the cellular processes underpinning tumorigenesis and chemoresistance. Mass spectrometryÃ¢â‚¬â€œbased proteomics revealed PRMT1 as a regulator of global arginine methylation changes in response to replicative stress in cancer cells. We show that, upon cisplatin, DNA-dependent protein kinase binds to- and phosphorylates PRMT1, inducing its chromatin recruitment and redirecting its enzymatic activity from soluble protein targets towards the histone substrate Arg3 of histone H4 (H4R3). On chromatin, DNA-PK/PRMT1 axis induces the Senescence-Associated Secretory Phenotype through the deposition of H4R3me2a at the pro-inflammatory gene promoters and by sustaining p65 binding to chromatin. Finally, PRMT1 inhibition reduced the clonogenic outgrowth of ovarian cancer cells exposed to low doses of CDDP and sensitized them to apoptosis. While unravelling a novel role of PRMT1 in replication stress response, our findings suggest the opportunity of targeting PRMT1 to sensitize cancer cells to genotoxic chemotherapeutics.

2020-01-15 | PXD014799 | Pride

The function of Wtap in N6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells [m6A-CLIP]

Project description:T cell antigen receptor (TCR) signaling controls the development, activation and survival of T cells by involving several layers and numerous mechanisms of gene regulation. N6-methyladenosine (m6A) is the most prevalent mRNA modification affecting splicing, translation and stability of transcripts. Here, we describe the Wtap protein as essential for m6A methyltransferase complex function and reveal its crucial role in TCR signaling. Wtap and m6A methyltransferase functions were required for the differentiation of thymocytes, control of activation-induced death of peripheral T cells and prevention of colitis by enabling gut RORγt+ regulatory T cell function. Transcriptome and epitranscriptomic analyses reveal that m6A modification destabilizes Orai1 and Ripk1 mRNAs. Lack of post-transcriptional repression of the encoded proteins correlated with increased store-operated calcium entry (SOCE) activity and diminished survival of T cells. These findings uncover how m6A modification impacts on TCR signal transduction and determines activation and survival of T cells.

2022-06-03 | GSE188853 | GEO

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