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Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B

ABSTRACT: Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B

PROVIDER: PRJNA1167640 | ENA |

REPOSITORIES: ENA

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Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B

Project description:Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with “epidrugs” is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.

2024-10-01 | GSE278498 | GEO

Effect of depletion of histone demethylases KDM6A and KDM6B on gene expression in the acute myeloid leukemia (AML) cell line U937 [RNA-seq]

Project description:To investigate the function of KDM6A and KDM6B in regulating gene expression in AML, we generated U937 cell lines having knockdown of either KDM6A, KDM6B or both using lentiviral shRNA. Control cells were generated using a scrambled shRNA. We then profiled gene expression using RNA-seq data obtained from the 3 knockdown cell lines compared with the control cell line.

2023-01-29 | GSE223609 | GEO

H3K27me3 demethylases maintain the transcriptional and epigenomic landscape of the intestinal epithelium [CHIP-seq]

Project description:To determine the contribution of H3K27me3 demethylases to intestinal homeostasis, an inducible mouse model was used to simultaneously ablate Kdm6a and Kdm6b expression from the intestinal epithelium. We then performed RNA-Seq gene expression analysis at two timepoints (7 days and 5 months) following induction of Kdm6a and Kdm6b ablation. Differential H3K27me3 regions were also identified using ChIP-Seq at one time point (7 days) following gene ablation.

2022-12-31 | GSE200975 | GEO

H3K27me3 demethylases maintain the transcriptional and epigenomic landscape of the intestinal epithelium [RNA-seq]

2022-12-31 | GSE200974 | GEO

KDM4B- and KDM6B-regulated genes in human mesenchymal stem cell osteogenic differentiation

Project description:To investigate how histone demethylases KDM4B and KDM6B may be involved in osteogenic commitment of mesenchymal stem cells (MSCs), we performed gene expression profiling and comparison on control, KDM4B- and KDM6B-knockdown MSCs at different stages of osteogenic differentiation. Human MSCs infected with scramble shRNAs, shRNAs against KDM4B or KDM6B are treated with BMP4/7 for 0, 4 and 24hrs. Total RNA were extracted from these 9 samples.

2012-07-31 | E-GEOD-36970 | biostudies-arrayexpress

Clonal Analyses of Refractory Testicular Germ Cell Tumors

Project description:We used DNA content-based flow cytometry to distinguish and isolate nuclei of clonal tumor populations from primary and metastatic refractory testicular germ cell tumors (TGCTs) tissues. We then interrogated each sorted tumor populationwith whole genome aCGH and next generation sequencing (NGS). we have explored the clonal basis of refractory TGCT by investigating distinct tumor populations that were present in each tumor. Notably this included resected primary tissues and treatment refractory metastases that arose after high dose chemotherapy. These results provide new knowledge regarding the role of clonal selection and selected genomic lesions in the resistance to chemotherapy in TGCT within this exceptional cohort.

2019-02-26 | GSE123464 | GEO

Decoding changes in chromatin accessibility mediated by KDM6 histone demethylases [ATAC-seq]

Project description:To interrogate the function of KDM6A and KDM6B in regulating genome accessibility, we generated U937 cell lines having knockdown of either KDM6A, KDM6B or both using lentiviral shRNA. We then profiled chromatin accessibility changes using ATAC-seq data obtained from the 3 knockdown cell lines compared with the wild type cell line.

2023-01-29 | GSE223608 | GEO

Clonal Analyses of Refractory Testicular Germ Cell Tumors

Project description:Clonal Analyses of Refractory Testicular Germ Cell Tumors

| PRJNA508792 | ENA

Characterizing the contrasting roles of JMJD3 and UTX histone demethylases in T cell acute lymphoblastic leukemia [shJMJD3_ChIP-seq]

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we abrogated the expression of JMJD3 (KDM6B) and UTX (KDM6A) H3K27me3 demethylases in human T-ALL lines and assayed for genome-wide changes in H3K27me3 levels. This piece of data was further integrated to expression changes using RNA sequencing in the same cells as well as ChIP-Sequencing analysis of H3K27me3 and JMJD3 genome-wide analysis from treatment of T-ALL lines with the GSKJ4 inhibitor. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3 as an oncogenice facilitator in leukemia whereas UTX seems to play a tumor suppressor role. Half to one million cells were treated with micrococcal nuclease (MNASE) to generate mononucleosomal particles and an adaptation of the Upstate ChIP protocol was used.

2014-10-01 | E-GEOD-56692 | biostudies-arrayexpress

Effect of depletion of histone demethylases KDM6A and KDM6B on gene expression in the acute myeloid leukemia (AML) cell line U937 [RNA-seq]

Project description:Effect of depletion of histone demethylases KDM6A and KDM6B on gene expression in the acute myeloid leukemia (AML) cell line U937 [RNA-seq]

| PRJNA926974 | ENA

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