BRD9 functions as a methylarginine reader to regulate AKT-EZH2 signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1193109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31576282_1.fastq.gz | Fastqsanger.gz | |||
| SRR31576282_2.fastq.gz | Fastqsanger.gz | |||
| SRR31576283_1.fastq.gz | Fastqsanger.gz | |||
| SRR31576283_2.fastq.gz | Fastqsanger.gz | |||
| SRR31576284_1.fastq.gz | Fastqsanger.gz |
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Project description:Arginine methylation is a common posttranslational modification that is catalyzed by a family of protein arginine methyltransferases. Recognition of methylarginine marks by effector proteins (“readers”) is a critical link between arginine methylation and various cellular processes. We recently identified methylation of AKT1 at Arg391 by PRMT5, but the reader for this methylation has yet to be characterized. Here, we show that BRD9, a reader of acetylated lysine, unexpectedly recognizes Arg391-methylated AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA-sequencing data shows that BRD9 and AKT co-regulate a hallmark transcriptional program in part through EZH2-mediated H3K27 trimethylation. Lastly, we find that inhibitors of BRD9 and EZH2 display synergistic effects on inhibition of cell viability and tumor growth. Together, our study demonstrates that BRD9 serves as a methylarginine reader to promote AKT-EZH2 oncogenic signaling and combined inhibition of BRD9 and EZH2 is a potential strategy for cancer therapy.
2025-03-18 | PXD058540 | Pride
Project description:Arginine methylation is a common posttranslational modification that is catalyzed by a family of protein arginine methyltransferases. Recognition of methylarginine marks by effector proteins (“readers”) is a critical link between arginine methylation and various cellular processes. We recently identified methylation of AKT1 at Arg391 by PRMT5, but the reader for this methylation has yet to be characterized. Here, we show that BRD9, a reader of acetylated lysine, unexpectedly recognizes Arg391-methylated AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA-sequencing data shows that BRD9 and AKT co-regulate a hallmark transcriptional program in part through EZH2-mediated H3K27 trimethylation. Lastly, we find that inhibitors of BRD9 and EZH2 display synergistic effects on inhibition of cell viability and tumor growth. Together, our study demonstrates that BRD9 serves as a methylarginine reader to promote AKT-EZH2 oncogenic signaling and combined inhibition of BRD9 and EZH2 is a potential strategy for cancer therapy.
2025-04-30 | GSE283326 | GEO
Project description:The lysine methyltransferase EZH2 is overexpressed in colorectal cancer (CRC) and has been found to be positively and negatively correlated with CRC patient survival depending on the study suggesting that EZH2 has a complex role in CRC. Here, we demonstrate that AKT-mediated EZH2 S21 phosphorylation induced EZH2 to trimethylate β-catenin at K49, which increased β-catenin’s binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin’s interaction with TCF1 and RNA polymerase II and resulted in a dramatic gain in genomic regions with β-catenin occupancy. Interestingly, EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC. Our results suggest that EZH2 inhibitors have tumor-inhibiting and promoting effects in CRC as they inhibit EZH2-mediated methylation of histone and non-histone targets like β-catenin.
2023-08-23 | GSE226587 | GEO
Project description:The lysine methyltransferase EZH2 is overexpressed in colorectal cancer (CRC) and has been found to be positively and negatively correlated with CRC patient survival depending on the study suggesting that EZH2 has a complex role in CRC. Here, we demonstrate that AKT-mediated EZH2 S21 phosphorylation induced EZH2 to trimethylate β-catenin at K49, which increased β-catenin’s binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin’s interaction with TCF1 and RNA polymerase II and resulted in a dramatic gain in genomic regions with β-catenin occupancy. Interestingly, EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC. Our results suggest that EZH2 inhibitors have tumor-inhibiting and promoting effects in CRC as they inhibit EZH2-mediated methylation of histone and non-histone targets like β-catenin.
2023-08-23 | GSE226584 | GEO
Project description:The lysine methyltransferase EZH2 is overexpressed in colorectal cancer (CRC) and has been found to be positively and negatively correlated with CRC patient survival depending on the study suggesting that EZH2 has a complex role in CRC. Here, we demonstrate that AKT-mediated EZH2 S21 phosphorylation induced EZH2 to trimethylate β-catenin at K49, which increased β-catenin’s binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin’s interaction with TCF1 and RNA polymerase II and resulted in a dramatic gain in genomic regions with β-catenin occupancy. Interestingly, EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC. Our results suggest that EZH2 inhibitors have tumor-inhibiting and promoting effects in CRC as they inhibit EZH2-mediated methylation of histone and non-histone targets like β-catenin.
2023-08-23 | GSE226588 | GEO
Project description:The goal of this study was to delineate the important EZH2 direct target genes that mediate the oncogenic properties of EZH2 in HCC. The EZH2 direct target genes in two HCC cell lines were identified by chromatin immunoprecipitation microarray (ChIP-chip) analysis and later confirmed by independent ChIP-PCR. The functions of the target genes were further examined. Two human HCC cell lines, Huh7 and PLC/PRF/5 (PLC5), were grown in DMEM supplemented with 10% fetal bovine serum. ChIP assays were performed using anti-EZH2 antibody. The immunoprecipitated and input DNA were used to probe the Agilent human ChIP-chip arrays.
2011-05-31 | E-GEOD-17733 | biostudies-arrayexpress
Project description:Our study shows that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI/SNF chromatin remodeling complex to sustain MYC transcription, rapid cell proliferation, and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain, which selectively suppressed the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9, which retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells conferred resistance to the anti-proliferative effects of our compound series, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2. Our study provides the first evidence for a role of BRD9 in cancer and reveals a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.
2016-05-01 | GSE79360 | GEO
Project description:Our study shows that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI/SNF chromatin remodeling complex to sustain MYC transcription, rapid cell proliferation, and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain, which selectively suppressed the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9, which retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells conferred resistance to the anti-proliferative effects of our compound series, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2. Our study provides the first evidence for a role of BRD9 in cancer and reveals a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.
2016-05-01 | GSE79284 | GEO
Project description:The goal of this study was to delineate the important EZH2 direct target genes that mediate the oncogenic properties of EZH2 in HCC. The EZH2 direct target genes in two HCC cell lines were identified by chromatin immunoprecipitation microarray (ChIP-chip) analysis and later confirmed by independent ChIP-PCR. The functions of the target genes were further examined.
2011-05-31 | GSE17733 | GEO
Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.
2023-01-25 | GSE214668 | GEO