Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA329526 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3929040_1.fastq.gz | Fastqsanger.gz | |||
| SRR3929040_2.fastq.gz | Fastqsanger.gz | |||
| SRR3929041_1.fastq.gz | Fastqsanger.gz | |||
| SRR3929041_2.fastq.gz | Fastqsanger.gz | |||
| SRR3929042_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
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Project description:In Interleukin (IL)-6 signalling, IL-6 site I binds to the IL-6 receptor (IL-6R) first, following by IL-6 site II interaction to domain 2/3 of gp130 to form premature trimeric IL-6:IL‑6R:gp130 receptor complexes. Formation of the mature hexameric receptor complex is then facilitated by the inter-trimeric interaction of IL-6 site III with domain 1 of the opposing gp130. The two gp130-associated Janus kinases (JAKs) trans-phosphorylate when their spatiotemporal pairing is correct, which causes the activation of STAT, ERK, and AKT pathways in a balanced manner. Since the intracellular domain (ICD) of IL-6R is not needed for STAT/ERK/AKT phosphorylation, we investigated the conditions under which a chimeric IL-6RECD-gp130TMD/ICD receptor protein confers biological activity. For IL‑6RECD‑gp130TMD/ICD, the extracellular domain (ECD) of IL-6R was fused to the transmembrane domain (TMD) and ICD of gp130. Co-expression of IL‑6RECD‑gp130TMD/ICD with signalling-deficient gp130 variants did not induce IL-6 signalling, suggesting that the assembly of hexameric complexes failed to dimerize the IL-6R-associated JAKs correctly. By mimicking the premature trimeric receptor complex, IL-6-mediated dimerization of IL-6RECD-gp130TMD/ICD with the single-cytokine-binding variant gp130DD1 induced signalling. Of note, IL-6 signalling via these synthetic gp130DD1:IL-6RECD-gp130TMD/ICD complexes resulted predominantly in STAT3 phosphorylation. A STAT3-dominated profile was also observed after IL-6-induced signalling mediated by a JAK-deficient IL‑6RECD‑gp130TMD/ICDDJAK variant in complex with the JAK-proficient but STAT/ERK/AKT-deficient gp130JAKDICD variant. Our data showed that effective ERK/AKT signalling could not be executed after intracellular domain swapping from gp130 to the IL-6R. Taken together, the chimeric IL-6R/gp130 receptor may be helpful in the creation of customized synthetic IL-6 signalling.
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Project description:The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2-phosphatase, PTEN. Despite huge investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signalling and constrained by pathway-feedback. In the absence of PTEN, the network is dramatically remodelled. A poorly understood, YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing, adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT-phosphorylation and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and SRC-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K-activation. hPLEKHS1-mRNA and activating-Y419-phosphorylation of hSRC correlated with PI3K-pathway activity in human prostate cancers. We propose that in PTEN-null cells, receptor-independent, SRC-dependent tyrosine-phosphorylation of PLEKHS1 creates positive-feedback that escapes homeostasis, drives PIP3-signalling and supports tumour progression.
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Project description:The high frequency of aberrant PI3K pathway activation in hormone receptor-positive (HR+) breast cancer has led to the development, clinical testing, and approval of the p110a-selective PI3K inhibitor alpelisib. The limited clinical efficacy of alpelisib and other PI3K inhibitors is partially attributed to the functional antagonism between PI3K and estrogen receptor (ER) signaling, which is mitigated via combined PI3K inhibition and endocrine therapy. We and others have previously demonstrated chromatin-associated mechanisms by which PI3K supports cancer development and antagonizes ER signaling through the modulation of the H3K4 methylation axis; inhibition of KDM5A promoter H3K4 demethylation and KMT2D/MLL4-directed enhancer H3K4 methylation. Here we show that inhibition of the H3K4 histone methyltransferase MLL1 in combination with PI3K inhibition impairs HR+ breast cancer clonogenicity and cell proliferation. While combined PI3K/MLL1 inhibition reduces PI3K/AKT signaling and H3K4 methylation, MLL1 inhibition increases PI3K/AKT signaling and dysregulates the expression of processes that lead to AKT activation. These data reveal a feedback loop between MLL1 and AKT whereby MLL1 inhibition reactivates AKT. We show that combined PI3K and MLL1 inhibition synergizes to cause cell death in in vitro and in vivo models of HR+ breast cancer, which is enhanced by the additional genetic ablation of the H3K4 methyltransferase and AKT target KMT2D/MLL4. Together, our data provide evidence of a feedback mechanism connecting histone methylation with AKT and may support the preclinical development and testing of pan-MLL inhibitors.
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Project description:The high frequency of aberrant PI3K pathway activation in hormone receptor-positive (HR+) breast cancer has led to the development, clinical testing, and approval of the p110a-selective PI3K inhibitor alpelisib. The limited clinical efficacy of alpelisib and other PI3K inhibitors is partially attributed to the functional antagonism between PI3K and estrogen receptor (ER) signaling, which is mitigated via combined PI3K inhibition and endocrine therapy. We and others have previously demonstrated chromatin-associated mechanisms by which PI3K supports cancer development and antagonizes ER signaling through the modulation of the H3K4 methylation axis; inhibition of KDM5A promoter H3K4 demethylation and KMT2D/MLL4-directed enhancer H3K4 methylation. Here we show that inhibition of the H3K4 histone methyltransferase MLL1 in combination with PI3K inhibition impairs HR+ breast cancer clonogenicity and cell proliferation. While combined PI3K/MLL1 inhibition reduces PI3K/AKT signaling and H3K4 methylation, MLL1 inhibition increases PI3K/AKT signaling and dysregulates the expression of processes that lead to AKT activation. These data reveal a feedback loop between MLL1 and AKT whereby MLL1 inhibition reactivates AKT. We show that combined PI3K and MLL1 inhibition synergizes to cause cell death in in vitro and in vivo models of HR+ breast cancer, which is enhanced by the additional genetic ablation of the H3K4 methyltransferase and AKT target KMT2D/MLL4. Together, our data provide evidence of a feedback mechanism connecting histone methylation with AKT and may support the preclinical development and testing of pan-MLL inhibitors.
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Project description:Activating mutations in PIK3CA, the gene encoding PI3Kα, are frequently found in estrogen receptor (ER+) breast cancer and the combination of the PI3K inhibitor alpelisib with the anti-ER agent fulvestrant is approved for therapy. We have uncovered a key role for the chromatin modifier KMT2D in regulating the ER-PI3K crosstalk. PI3Kα effectors, AKT and SGK, negatively regulate KMT2D through S1331 phosphorylation. When PI3K is inhibited, this regulatory event is lost, leading to increased chromatin recruitment of KMT2D and an upregulation of ER-dependent transcription. Here we discovered a previously undescribed methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding. Accordingly, loss of SMYD2 abrogates alpelisib-induced changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Methyl dead knock-in clones of KMT2D phenocopy many of the effects of SMYD2 inhibition on cell and tumor growth, drug response, and transcriptional output. Together, our findings uncover a regulatory cross-talk between posttranslational modifications that plays an important role in fine-tuning the functions of KMT2D at the chromatin. This provides a rationale for epigenetic therapy using SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors for the treatment of ER+/PIK3CA mutant breast cancer.
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Project description:Activating mutations in PIK3CA, the gene encoding PI3Kα, are frequently found in estrogen receptor (ER+) breast cancer and the combination of the PI3K inhibitor alpelisib with the anti-ER agent fulvestrant is approved for therapy. We have uncovered a key role for the chromatin modifier KMT2D in regulating the ER-PI3K crosstalk. PI3Kα effectors, AKT and SGK, negatively regulate KMT2D through S1331 phosphorylation. When PI3K is inhibited, this regulatory event is lost, leading to increased chromatin recruitment of KMT2D and an upregulation of ER-dependent transcription. Here we discovered a previously undescribed methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding. Accordingly, loss of SMYD2 abrogates alpelisib-induced changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Methyl dead knock-in clones of KMT2D phenocopy many of the effects of SMYD2 inhibition on cell and tumor growth, drug response, and transcriptional output. Together, our findings uncover a regulatory cross-talk between posttranslational modifications that plays an important role in fine-tuning the functions of KMT2D at the chromatin. This provides a rationale for epigenetic therapy using SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors for the treatment of ER+/PIK3CA mutant breast cancer.
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Project description:Activating mutations in PIK3CA, the gene encoding PI3Kα, are frequently found in estrogen receptor (ER+) breast cancer and the combination of the PI3K inhibitor alpelisib with the anti-ER agent fulvestrant is approved for therapy. We have uncovered a key role for the chromatin modifier KMT2D in regulating the ER-PI3K crosstalk. PI3Kα effectors, AKT and SGK, negatively regulate KMT2D through S1331 phosphorylation. When PI3K is inhibited, this regulatory event is lost, leading to increased chromatin recruitment of KMT2D and an upregulation of ER-dependent transcription. Here we discovered a previously undescribed methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding. Accordingly, loss of SMYD2 abrogates alpelisib-induced changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Methyl dead knock-in clones of KMT2D phenocopy many of the effects of SMYD2 inhibition on cell and tumor growth, drug response, and transcriptional output. Together, our findings uncover a regulatory cross-talk between posttranslational modifications that plays an important role in fine-tuning the functions of KMT2D at the chromatin. This provides a rationale for epigenetic therapy using SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors for the treatment of ER+/PIK3CA mutant breast cancer.
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