Methylation-induced conformational switch enables ERG oncogenic activation and prostate cancer progression
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ABSTRACT:
PROVIDER: PRJNA669019 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12818310.fastq.gz | Fastqsanger.gz | |||
| SRR12818311.fastq.gz | Fastqsanger.gz |
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Project description:The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer but its role in disease progression is still debated. In this study, we uncovered a novel molecular mechanism promoting progression in ERG-fusion positive prostate cancer. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 mono- methylation prevents intra-domain interactions, favors DNA binding and promotes ERG transcriptional and oncogenic activity in cellular and mouse models. Consistently with the involvement in ERG oncogenesis, we found that K362 methylation was associated with disease progression in ERG transgenic mouse models and was enhanced by PTEN deficiency and AKT activation, which promoted EZH2 substrate switching from histone H3K27 to ERG. Conversely, EZH2 inhibition blocked ERG methylation along with ERG-induced transcriptional and phenotypic reprogramming in cell cultures and ERG/PTEN mice. We found that ERG and EZH2 co-occupy several genomic regions forming prevalently co-activating complexes. The network of ERG/EZH2 co-regulated target genes was enriched of functionally aggressive features and was associated preferentially with concomitant ERG gain and PTEN loss, castration-resistance and adverse clinical outcome in prostate cancer patients. Collectively, these findings identify ERG methylation as a novel post-translational modification sustaining disease progression in ERG-positive prostate cancers. Our data also provide an attractive rationale for developing molecularly targeted therapeutics to antagonize ERG oncogenic activity.
2021-04-16 | GSE159471 | GEO
Project description:i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists
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Project description:Bernasocchi T, El Tekle G, Bolis M, Svinkina T, Zoma M, Rinaldi A, Ceserani V, Janouskova H, Schram P, Carbone G, Alimonti A, Moch H, Carr SA, Udeshi ND, Theurillat JP. 2018.
While the co-operation of cancer driver genes in tumorigenesis has been studied, little is known about the interplay of driver mutations that never co-occur within the same cancer cells. The latter scenario has been identified in prostate cancer where recurrent gene fusions involving the oncogenic ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are strictly mutually exclusive. Nevertheless, the underlying basis of this observation is poorly understood. Here, we show that ERG and mutant SPOP, even though oncogenic on their own, are together synthetic sick. At the molecular level, both driver genes inhibit each other in a reciprocal manner. In ERG-driven tumors, wild type SPOP is required to dampen androgen receptor (AR) signaling and sustain ERG activity in part through its ability to degrade the bromodomain histone reader ZMYND11. Consequently, loss-of-function mutations in SPOP unleash excessive AR signaling and reduce ERG function. Conversely, oncogenic androgen receptor signaling driven by mutant SPOP is repressed by ERG. The incompatibility of mutant SPOP and ERG may help to understand why SPOP mutant tumors frequently harbor gene deletions in the chromatin-modifying enzyme CHD1. We find that mutant SPOP promotes the generation of ERG rearrangements in a CHD1-dependent manner. Thus, CHD1 gene deletions may protect SPOP-mutant tumors from ERG-mediated growth inhibition. Taken together, our findings reveal the existence of divergent and incompatible paths towards prostate cancer that converge on SPOP function.
| MSV000082915 | MassIVE
Project description:The ERG gene belongs to the ETS family of transcription factors and has been found involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG,. We found that all the three ERG fusions significantly up-regulate PIM-1 expression in the NIH-3T3 cell line. PIM-1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM-1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM-1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM-1 induction. A significant association between ERG and PIM-1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM-1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM-1 expression. The up-regulation of PIM-1 induced by tERG over-expression significantly modified CyclinB1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after 24hrs of taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM-1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability. NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG together with the empty vector where profiled in triplicate. Quality control using NUSE and RLE plots identified one array as problematic (R540_TMP-ERG_P1) which was removed.
2011-11-30 | E-GEOD-32481 | biostudies-arrayexpress
Project description:Histone H3 lysine 9 methylation (H3K9me) mediates heterochromatic gene silencing and is important for genome stability and the regulation of gene expression. The establishment and epigenetic maintenance of heterochromatin involve the recruitment of H3K9 methyltransferases to specific sites on DNA, followed by the recognition of pre-existing H3K9me by the methyltransferase and methylation of proximal histone H3. This positive feedback loop must be tightly regulated to prevent deleterious epigenetic gene silencing. Extrinsic anti-silencing mechanisms involving histone demethylation or boundary elements help limit the spread of inappropriate H3K9me. However, how H3K9 methyltransferase activity is locally restricted or prevented from initiating random H3K9me—which would lead to aberrant gene silencing and epigenetic instability—is not fully understood. Here we reveal an autoinhibited conformation in the conserved H3K9 methyltransferase Clr4 (Suv39h) of the fission yeast Schizosaccharomyces pombe that has a critical role in preventing aberrant heterochromatin formation. Biochemical and X-ray crystallographic data show that an internal loop in Clr4 inhibits the catalytic activity of this enzyme by blocking the histone H3K9 substrate-binding pocket, and that automethylation of specific lysines in this loop promotes a conformational switch that enhances the H3K9me activity of Clr4. Mutations that are predicted to disrupt this regulation lead to aberrant H3K9me, loss of heterochromatin domains, and growth inhibition, demonstrating the importance of the intrinsic inhibition and auto-activation of Clr4 in regulating the deposition of H3K9me and in preventing epigenetic instability. Together, conservation of the Clr4 autoregulatory loop in other H3K9 methyltransferases and the automethylation of a corresponding lysine in the human SUV39H2 homologue suggest that the mechanism described here is broadly conserved.
2018-07-17 | GSE102905 | GEO
Project description:Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer
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Project description:Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG up-regulation in approximately 50% of prostate cancers. Studies to date have demonstrated important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. To address these questions, we generated engineered LNCaP cells with ERG overexpression followed by LEF1 knockdown as well as control cell lines. To further investigate the role of LEF1 in ERG fusion positive samples, we also knockdown ERG in VCaP cell line.
2013-05-29 | GSE47423 | GEO
Project description:Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG up-regulation in approximately 50% of prostate cancers. Studies to date have demonstrated important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. To address these questions, we generated engineered LNCaP cells with ERG overexpression followed by LEF1 knockdown as well as control cell lines. To further investigate the role of LEF1 in ERG fusion positive samples, we also knockdown ERG in VCaP cell line. We performed microarray analysis on LNCaP cells with ERG overexpression followed by LEF1 knockdown using siRNA. We also knockdown endogenous ERG in fusion-positive cell line VCaP.
2013-05-29 | E-GEOD-47423 | biostudies-arrayexpress
Project description:We compared the genome occupancy for FLAG-tagged versions of the ETS factors ERG and EHF in the normal prostate epithelial cell line RWPE1. Our in vitro binding studies support a model whereby oncogenic ETS factors like ERG bind cooperativly with AP1 factors at closly spaced ETS-AP1 sites, while certain non-oncogenic factors like EHF bind anti-cooperatively with AP1 at the same sites. ETS and AP1 binding motifs were enriched in both ChIP datasets, but the ERG-FLAG bound reginos contained a much higher percentage of ETS-AP1 sites spaced in close proximity, consistent with our in vitro binding data.
2018-05-10 | GSE114241 | GEO
Project description:The ERG gene belongs to the ETS family of transcription factors and has been found involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG,. We found that all the three ERG fusions significantly up-regulate PIM-1 expression in the NIH-3T3 cell line. PIM-1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM-1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM-1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM-1 induction. A significant association between ERG and PIM-1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM-1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM-1 expression. The up-regulation of PIM-1 induced by tERG over-expression significantly modified CyclinB1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after 24hrs of taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM-1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability.
2011-11-30 | GSE32481 | GEO