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DRAIC mediates hnRNPA2B1 stability and m6A-modified IGF1R instability to inhibit tumor progression [m6A-seq]

ABSTRACT: Both N6-methyladenosine (m6A) mediates RNA fates and ubiquitin mediates protein fates play an important role in either physiology or pathology including cancer, yet how long noncoding RNAs (lncRNAs) are involved in a link of molecular fate between m6A and ubiquitin remains unknown. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) to suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitin and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-type 1 insulin-like growth factor receptor (IGF1R) to lead to inhibition of ccRCC progression. Moreover, four m6A modification sites of IGF1R are identified and results in its mRNA degradation. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA expression in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244892 | GEO | 2024/01/07

REPOSITORIES: GEO

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DRAIC mediates hnRNPA2B1 stability and m6A-modified IGF1R instability to inhibit tumor progression

Project description:Both N6-methyladenosine (m6A) mediates RNA fates and ubiquitin mediates protein fates play an important role in either physiology or pathology including cancer, yet how long noncoding RNAs (lncRNAs) are involved in a link of molecular fate between m6A and ubiquitin remains unknown. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) to suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitin and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-type 1 insulin-like growth factor receptor (IGF1R) to lead to inhibition of ccRCC progression. Moreover, four m6A modification sites of IGF1R are identified and results in its mRNA degradation. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA expression in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.

2024-04-26 | GSE262500 | GEO

DRAIC mediates hnRNPA2B1 stability and m6A-modified IGF1R instability to inhibit tumor progression [RNA-seq]

2024-01-07 | GSE244891 | GEO

IGF2BP1 stabilizes OTX2 mRNA in an m6A-dependent manner to restrict human germ cell fate by repressing TFAP2C

Project description:N6-methyladenosine (m6A) is the most abundant and reversible modification on messenger RNAs. The differential m6A profiles in different cell types are installed by writers (such as METTL3) and removed by erasers (such as FTO). The m6A-modified RNAs are recognized by readers to trigger downstream regulation of RNA metabolism, eventually contributing to the regulation of cell fates. Primordial germ cells (PGCs) are specified early during embryogenesis and establish the germ cell lineage for transmitting genetic and epigenetic information from parents to offspring. Defects in the establishment of germline may lead to infertility, germ cell tumors, and birth defects. Despite extensive research, the m6A-mediated epigenetic regulation of the specification of PGCs remains elusive. In this study, we discovered that knock-out of m6A writer or over-expression of erasers leads to increased percentage of human PGC-like cells (hPGCLCs) induced from embryonic stem cells. We identified the m6A reader IGF2BP1 as the key factor for restricting hPGCLC fate induction by stabilizing OTX2 mRNAs in an m6A-dependent manner. Moreover, we discovered that OTX2 suppresses TFAP2C during germ cell lineage specification. In summary, we characterized the m6A-IGF2BP1-OTX2-TFAP2C axis in restricting the specification of human germ cell fate.

2024-04-30 | PXD051996 |

MeRIP-Seq map HNRNPA2B1 maintains MM tumorigenicity by m6A dependent stabilizing of mRNA

Project description:To investigated the mechanism of HNRNPA2B1 in MM tumorigenesis, performed m6A IP seq analysis (MeRIP-Seq) to identify the expression changes in stable HNRNPA2B1-knockdown MM cells.60 genes m6A with over 2-fold expression change in shHNRNPA2B compared with control in both ARP1 and H929 cells.44 differentially expressed genes (P<0.05) in both m6A and transcription in shHNRNPA2B compared with control in ARP1 cell.

2021-11-30 | GSE162745 | GEO

FBXO11-Mediated Proteolysis of BAHD1 Relieves PRC2-dependent Transcriptional Repression in Erythropoiesis

Project description:The histone mark H3K27me3 and its reader/writer Polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for tissue development but poorly understood. Here we show that the E3 ubiquitin ligase FBXO11 relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate BAHD1, an H3K27me3 reader that recruits transcriptional co-repressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks (activating H3K4me3 and repressive H3K27me3), bind BAHD1, and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2 and depletion of either component restores FBXO11-deficient erythroid gene expression. Previous studies showed that FBXO11 promotes B-cell development and inhibits lymphomagenesis by degrading the transcriptional repressor BCL6. We show that in aggressive B-cell lymphoma lines, depletion of FBXO11 causes the accumulation of both BCL6 and BAHD1, and that suppression of BAHD1 slows cell expansion. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at developmentally poised bivalent genes during erythropoiesis. The FBXO11-BAHD1 regulatory axis may function in other developmental pathways, including B-lymphopoiesis and lymphomagenesis.

2020-12-31 | GSE115357 | GEO

Single-nucleotide resolution mapping of m6A and m6Am throughout the transcriptome

Project description:N6-methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA and has been linked to diverse effects on mRNA fate and function. Current m6A mapping approaches rely on immunoprecipitation of m6A-containing RNA fragments to identify regions of transcripts that contain m6A. This approach localizes m6A residues to 100-200 nt-long regions of transcripts. The precise position of m6A in mRNAs cannot be identified on a transcriptome-wide level because there are no chemical methods to distinguish between m6A and adenosine. Here we show that anti-m6A antibodies can induce specific mutational signatures at m6A residues after ultraviolet light-induced antibody-RNA crosslinking and reverse transcription. Similarly, we find these antibodies induce mutational signatures at N6, 2’-O-dimethyladenosine (m6Am), a nucleotide found at the first encoded position of certain mRNAs. Using these mutational signatures, we map m6A and m6Am at single-nucleotide resolution in human and mouse mRNA and identify snoRNAs as a novel class of m6A-containing ncRNAs. UV-crosslinking and immunoprecipitation with m6A-specific antibodies was used to map m6A and m6Am in cellular RNA with single nucleotide resolution.

2015-06-29 | E-GEOD-63753 | biostudies-arrayexpress

Arabidopsis Messenger RNA N6-methyladenosine Demethylation Regulates Plant Development

Project description:N6-methyladenosine (m6A) is the most abundant internal modification in the messenger RNA (mRNA) of all higher eukaryotes. This modification has been shown to be reversible in mammals; it is installed by a methyltransferase heterodimer complex of METTL3 and METTL14 bound with WTAP, and reversed by iron(II)- and Î±-ketoglutarate-dependent demethylases FTO and ALKBH5. This modification exhibits significant functional roles in various biological processes. The m6A modification as a RNA mark is recognized by reader proteins, such as YTH domain family proteins and HNRNPA2B1; m6A can also act as a structure switch to affect RNA-protein interactions for biological regulation. In Arabidopsis thaliana, the methyltransferase subunit MTA (the plant orthologue of human METTL3, encoded by At4g10760) was well characterized and FIP37 (the plant orthologue of human WTAP) was first identified as the interacting partner of MTA. Here we report the discovery and characterization of reversible m6A methylation mediated by AtALKBH10B (encoded by At4g02940) in A. thaliana, and noticeable roles of this RNA demethylase in affecting plant development and floral transition. Our findings reveal potential broad functions of reversible mRNA methylation in plants. m6A peaks were identified from wild type Columbia-0 and atalkbh10b-1 mutant in two biological replicates

2016-03-24 | E-GEOD-79523 | biostudies-arrayexpress

Identification of HNRNPA2B1-regulated miRNA targets in breast cancer cells

Project description:Higher N(6)-methyladenosine (m6A) was identified in selected primary microRNAs (pri-miRNAs) as associated with increased levels of the corresponding mature miRNA in MDA-MB-231 triple negative breast cancer (TNBC) cells (PMID: 25799998). HNRNPA2B1 is a reader of the m6A mark in pri-miRNAs and interacts directly with DGCR8 (a component of the nuclear DROSHA complex) to promote processing of pri-miRNAs to precursor-miRNAs (pre-miRNAs) (PMID: 26321680). We have preliminary data showing that HNRNPA2B1 is increased in TAM-resistant, ERα+ LCC9 cells derived from TAM-sensitive, ERα+ MCF-7 breast cancer cells. We found that high HNRNPA2B1 transcript levels in primary breast tumors are associated with reduced overall survival. We postulate that an increase in HNRNPA2B1 targets its binding to additional pri-miRNAs (not normally bound under wild type conditions), resulting in an increase in miRNAs, including those that promote TAM-resistance.

2019-07-25 | GSE122634 | GEO

Frequent mutations of FBXO11 identify BCL6 as a therapeutic target in Burkitt Lymphoma

Project description:BCL6 is a key oncogene in lymphoma pathogenesis. The expression of BCL6 in lymphoid cells can be deregulated by several mechanisms, including chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a major ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in diffuse large B-cell lymphoma (DLBCL). In this work, we found that FBXO11 is frequently mutated in Burkitt lymphoma (BL) but rarely mutated in other BCL6-positive lymphomas, such as follicular lymphoma (FL). All mutations tested impaired FBXO11 mediated BCL6 degradation and FBXO11 knock-out completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of one copy or both copies of FBXO11 in c-Myc-driven B cell lymphoma in mice accelerated lymphomagenesis, genetically confirming that FBXO11 is a haplo-insufficient oncosuppressor in lymphoma. In both FBOX11 WT and deficient BL mouse and human cell lines, blockade of BCL6 via a specific degrader or BCL6 inhibitors, impaired lymphoma growth in vitro and in vivo, an effect further enhanced by co-inhibition of c-Myc activity. Overall these findings not only establish FBXO11 as one of the most frequently mutated genes in BL, but also elucidate its biological functions in lymphomagenesis and thereby identify BCL6 as a specific therapeutic target in BL.

2021-12-31 | GSE159303 | GEO

KIAA1429 promotes cell proliferation by regulating MYC messenger RNA in clear cell renal cell carcinoma

Project description:KIAA1429 is an integral component of the m6A methyltransferase complex, essential for facilitating the interaction between the catalytic core components METTL3 and METTL14. However, the mechanisms by which KIAA1429 influences clear cell Renal cell carcinoma (ccRCC) remain incompletely elucidated. Analysis of the TCGA and GEO database confirmed that KIAA1429 was significantly upregulated in ccRCC samples, which correlated with poor survival. Additionally, qRT-PCR, Western Blot and IHC detection revealed significantly upregulated levels of KIAA1429 in ccRCC tissues. Moreover, multivariable Cox regression analysis showed that patients with ccRCC with high KIAA1429 expression had a poor clinical prognosis. Notably, silencing KIAA1429 significantly inhibited the proliferation, migration and invasion of ccRCC cells. Similarly, KIAA1429 knockdown also significantly inhibited the growth of ccRCC cells in nude mice. Mechanistically, KIAA1429 silencing significantly reduced the overall level of m6A in, the stability of MYC mRNA and the mRNA and protein expressions of MYC in ccRCC cells. Furthermore, RIP-qRT-PCR experiments showed that KIAA1429 could directly bind to MYC mRNA. MeRIP assay revealed that KIAA1429 knockdown resulted in a significant decrease in the m6A level of MYC mRNA in ccRCC cells. In conclusion, KIAA1429 regulates the proliferation, migration and invasion of ccRCC cells by stabilizing MYC mRNA in an m6A-dependent manner. Therefore, targeting the KIAA1429-MYC signalling pathway emerges as a potential strategy for the treatment of renal cell carcinoma.

2024-09-10 | GSE276431 | GEO

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