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Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer

ABSTRACT: Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer

PROVIDER: PRJNA330537 | ENA |

REPOSITORIES: ENA

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Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer [ChIP-seq]

Project description:We aim to elucidate the mechanisms of how PI3K inhibition is promoting oestrogen receptor (ER) activation and ER dependency in breast cancer.

2017-03-01 | GSE84593 | GEO

Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer [ATAC-seq]

Project description:We aim to elucidate the mechanisms of how PI3K inhibition is promoting oestrogen receptor (ER) activation and ER dependency in breast cancer.

2017-03-01 | GSE84515 | GEO

Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer

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2017-03-01 | GSE84594 | GEO

Regulation of KMT2D by PI(3)K/AKT signalling orchestrates oestrogen receptor mediated transcriptional activation in breast cancer

Project description:We aim to elucidate the mechanisms of how PI3K inhibition is promoting estrogen receptor (ER) activation and ER dependency in breast cancer.

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RNA-seq of KMT2D Knockout and KMT2D WT melanoma in mice

Project description:Somatic mutations in various epigenetic regulators, including histone methyltransferases KMT2C and KMT2D, have emerged as important cancer-driving events. However, the mechanism of action and therapeutic vulnerability imparted by these mutations remain poorly understood. We identified KMT2D and 8 other epigenetic regulators as potential suppressors to melanoma initiation through an in vivo pooled epigenome-focused RNAi screen. Loss of KMT2D, which exhibits somatic mutations in human melanoma and other cancers, drastically enhanced melanoma progression in xenograft models and a BRAFV600E-driven genetically engineered mouse model of melanoma. Epigenome profiling of 6 histone marks and chromatin state alterations showed substantial reprogramming of H3K4me1- and H3K27ac-marked active enhancer states in KMT2D mutant tumors. Energy metabolic pathways such as glycolysis, OxPhos and TCA/electron transport showed high degree of deregulation which was confirmed with metabolic profiling. Pharmacological abrogation of glycolysis led to reduced proliferation and tumorigenesis preferentially in KMT2D mutant cells. Mechanistically, we find that enhancer loss at IGFBPs increases IGF signaling and downstream AKT phosphorylation that leads to upregulation of metabolic pathways rendering KMT2D mutant cells dependent on these energy metabolism pathways for their higher growth potential. Overall, we present evidence that KMT2D mutations promote tumorigenesis by reprogramming energy metabolism pathways through enhancer reprogramming.

2020-11-16 | GSE116852 | GEO

Genome-wide maps of chromatin state in KMT2D Knockout and KMT2D WT melanoma in mice

2020-11-16 | GSE116851 | GEO

Methylation of the epigenetic regulator KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer [KMT2D_KI_RNA]

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.

2024-05-04 | GSE253958 | GEO

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