Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B DOI Creative Commons
Doha Shokry,

Mehwish Khan,

Christine Powell

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 18, 2024

Abstract 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 the young TGCT patient population providing rationale to decrease exposure. In contrast genetic alterations, recent evidence suggests that epigenetics is major driving factor for formation, progression, response chemotherapy. Hence, targeting epigenetic pathways “epidrugs” one potential relatively unexplored strategy advance treatment beyond cisplatin. this report, we demonstrate first time polycomb demethylases KDM6A KDM6B epidrug GSK-J4 treat both cisplatin-sensitive -resistant TGCTs. While had minimal effects alone on tumor growth vivo, it dramatically sensitized TGCTs We validated KDM6A/KDM6B target since depletion similar effect cisplatin-mediated anti-tumor activity transcriptome alterations. Pharmacologic potentiated or primed p53-dominant transcriptional cisplatin, also basal activation p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, methyltransferases, were repressed only KDM6A/KDM6B-targeted cells, implying inhibition sets stage extensive remodeling cells upon treatment. Our findings new potent pharmacologic treating resistant warrants clinical development.

Language: Английский

Synthesis and application of small molecules approved for the treatment of lymphoma DOI

Yuanyuan Guo,

Jingyi Zhang, Jinfeng Sun

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 261, P. 115835 - 115835

Published: Sept. 30, 2023

Language: Английский

Citations

2
Clinical Significance of Upregulation of EZH1 Expression in Hepatocellular Carcinoma Tissues DOI Open Access
Siyu Chen, Jian‐Di Li, Zhi‐Guang Huang

et al.

Journal of Gastrointestinal and Liver Diseases, Journal Year: 2024, Volume and Issue: 33(1), P. 44 - 56

Published: March 30, 2024

Background and Aims: The incidence mortality of hepatocellular carcinoma (HCC) are increasing. It is urgent to develop more effective HCC biomarkers for diagnosis treatment. This project intends verify the expression enhancer zeste 1 polycomb repressive complex 2 subunit (EZH1) its mechanism in HCC. Methods: study integrates global microarray high-throughput sequencing datasets, combined with internal immunohistochemistry, analyze prognostic value EZH1 Functional enrichment analysis was conducted investigate transcriptional targets, which were achieved by intersecting over-expressed genes, co-expressed genes putative targets. relationship between anticancer drugs detected drug sensitivity analysis. Results: In this study, 84 datasets from 40 platforms (3,926 samples 3,428 non-cancerous liver tissues) included show high Immunohistochemistry 159 62 non-HCC confirmed level. patients had worse survival prognoses. Gene ontology Reactome revealed that metabolism-related pathways, including autophagy, critical Interestingly, as one potential autophagy-related 7 (ATG7) appeared above pathways. ATG7 positively correlated EZH1, upregulated HCC, mediated poor prognosis. Upregulation found be contact anti-tumor resistance. Conclusions: upregulation can promote occurrence lead clinical progression resistance; these effects may regulating ATG7.

Language: Английский

Citations

0
Decline in corepressor CNOT1 in the pregnant myometrium near term impairs progesterone receptor function and increases contractile gene expression DOI Creative Commons

Youn-Tae Kwak,

Alina P. Montalbano, Andrew M. Kelleher

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(7), P. 107484 - 107484

Published: June 18, 2024

Language: Английский

Citations

0
A novel EZH1/2 dual inhibitor inhibits GCB DLBCL through Cell Cycle Regulation and M2 Tumor-Associated Macrophage Polarization DOI Creative Commons
Ran An, Zhimeng Zhang, Dongli Zhang

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 107788 - 107788

Published: Sept. 1, 2024

Language: Английский

Citations

0
Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B DOI Creative Commons
Doha Shokry,

Mehwish Khan,

Christine Powell

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 18, 2024

Abstract 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 the young TGCT patient population providing rationale to decrease exposure. In contrast genetic alterations, recent evidence suggests that epigenetics is major driving factor for formation, progression, response chemotherapy. Hence, targeting epigenetic pathways “epidrugs” one potential relatively unexplored strategy advance treatment beyond cisplatin. this report, we demonstrate first time polycomb demethylases KDM6A KDM6B epidrug GSK-J4 treat both cisplatin-sensitive -resistant TGCTs. While had minimal effects alone on tumor growth vivo, it dramatically sensitized TGCTs We validated KDM6A/KDM6B target since depletion similar effect cisplatin-mediated anti-tumor activity transcriptome alterations. Pharmacologic potentiated or primed p53-dominant transcriptional cisplatin, also basal activation p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, methyltransferases, were repressed only KDM6A/KDM6B-targeted cells, implying inhibition sets stage extensive remodeling cells upon treatment. Our findings new potent pharmacologic treating resistant warrants clinical development.

Language: Английский

Citations

0