Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA330542 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3931730.fastq.gz | Fastqsanger.gz | |||
| SRR3931731.fastq.gz | Fastqsanger.gz | |||
| SRR3931732.fastq.gz | Fastqsanger.gz | |||
| SRR3931733.fastq.gz | Fastqsanger.gz | |||
| SRR3931734.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 10 |
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Project description:Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer
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Project description:The vast majority of all breast cancers are driven by oestrogen receptor alpha (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients. However, resistance is common and tumours progress despite years of systemic endocrine suppression. Periodic fasting enhances the efficacy of standard endocrine drugs and delay acquired resistance to them, although the underlying mechanisms remain unclear. Here, we show that fasting, in combination with endocrine therapy, induces extensive epigenetic reprogramming in hormone receptor-positive (HR+) breast cancer xenografts, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor (PR) signalling, and impairment of activator protein-1 (AP-1) family activity. GR-driven gene programs were selectively activated after fasting, and GR knockout perturbed the beneficial effects of fasting in combination with tamoxifen, in vivo. Exogenous administration of GR-ligands fully recapitulated the observed fasting-enhanced anti-oestrogen action, resulting in tumour regression. Finally, elevated progesterone and cortisol levels were detected in the blood of breast cancer patients after fasting, thus providing clinical validation of our animal findings. Our results indicate GR activation to play a pivotal role in fasting’s ability to enhance endocrine drug activity against hormone-receptor positive breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this condition.
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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:The vast majority of all breast cancers are driven by oestrogen receptor alpha (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients. However, resistance is common and tumours progress despite years of systemic endocrine suppression. Periodic fasting enhances the efficacy of standard endocrine drugs and delay acquired resistance to them, although the underlying mechanisms remain unclear. Here, we show that fasting, in combination with endocrine therapy, induces extensive epigenetic reprogramming in hormone receptor-positive (HR+) breast cancer xenografts, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor (PR) signalling, and impairment of activator protein-1 (AP-1) family activity. GR-driven gene programs were selectively activated after fasting, and GR knockout perturbed the beneficial effects of fasting in combination with tamoxifen, in vivo. Exogenous administration of GR-ligands fully recapitulated the observed fasting-enhanced anti-oestrogen action, resulting in tumour regression. Finally, elevated progesterone and cortisol levels were detected in the blood of breast cancer patients after fasting, thus providing clinical validation of our animal findings. Our results indicate GR activation to play a pivotal role in fasting’s ability to enhance endocrine drug activity against hormone-receptor positive breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this condition.
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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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