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Methylation of the epigenetic regulator KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer [KMT2D_ChIP_seq]

ABSTRACT: Methylation of the epigenetic regulator KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer [KMT2D_ChIP_seq]

PROVIDER: PRJNA1074389 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27906932_1.fastq.gz	Fastqsanger.gz
	SRR27906932_2.fastq.gz	Fastqsanger.gz
	SRR27906933_1.fastq.gz	Fastqsanger.gz
	SRR27906933_2.fastq.gz	Fastqsanger.gz
	SRR27906934_1.fastq.gz	Fastqsanger.gz

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Methylation of the epigenetic regulator KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer [SMYD2_KD_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 | GSE253957 | GEO

Methylation of the epigenetic regulator KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer [KMT2D_ChIP_seq]

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

2024-05-04 | GSE253958 | GEO

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

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

| PRJNA1068003 | ENA

Methylation of the epigenetic regulator KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer [SMYD2_KD_RNA]

Project description:Methylation of the epigenetic regulator KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer [SMYD2_KD_RNA]

| PRJNA1068001 | ENA

Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.

Project description:Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated 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. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

| S-EPMC11265541 | biostudies-literature

SMYD2 overexpression in Neonatal rat ventricular cardiomyocytes

Project description:From this array we would like to know the role of Smyd2 on hypoxic regulated genes mainly angiogenic pathway. We performed overexpressions of Smyd2 and beta galactosidase by adenoviral approach and knockdown of HIF1 and Smyd2 were performed by lipofectamine RNAiMAX.Cardiomyocytes were isolated from neonatal rats at P3.

2025-03-01 | GSE256036 | GEO

The effects of SMYD2 overexpression on ectopic RB in SAOS cells

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Genome-wide maps of chromatin state of Smyd2 binding in renal epithelial cells

Project description:To identify potential transcriptional targets of Smyd2, we performed ChIP-sequencing (ChIP-seq) analysis in renal epithelial cells with an anti-Smyd2 antibody. We identified 91 potential Smyd2 target genes in Pkd1 wild type MEK cells and 116 potential Smyd2 target genes in Pkd1 null MEK cells. There were 14 genes identified in both Pkd1 wild type and null MEK cells. Thus, the number of potential Smyd2 target genes in Pkd1 null MEK cells are 116 - 14 = 102 genes

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The effects of SMYD2 overexpression on ectopic RB in SAOS cells

Project description:Expression analysis of wild-type SAOS cells and SAOS cells transiently transfected with RB, SMYD2, or RB and SMYD2. Four samples of wild-type, rb1, smyd2 and rb1-smyd2 were analyzed on the Human Genome U133 Plus 2.0 array.

2011-01-01 | E-GEOD-22842 | biostudies-arrayexpress

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