Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B.
Testicular Neoplasms
/ drug therapy
Neoplasms, Germ Cell and Embryonal
/ drug therapy
Humans
Cisplatin
/ pharmacology
Jumonji Domain-Containing Histone Demethylases
/ metabolism
Histone Demethylases
/ metabolism
Cell Line, Tumor
Male
Drug Resistance, Neoplasm
/ drug effects
Animals
Benzazepines
/ pharmacology
Polycomb-Group Proteins
/ metabolism
Pyrimidines
/ pharmacology
Mice
Nuclear Proteins
/ metabolism
Gene Expression Regulation, Neoplastic
/ drug effects
Antineoplastic Agents
/ pharmacology
Chemotherapy resistance
Cisplatin
Epigenetics
GSK-126
GSK-J4
Polycomb
Preclinical
Testicular cancer
Transcriptomics
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
31 Oct 2024
31 Oct 2024
Historique:
received:
27
08
2024
accepted:
27
10
2024
medline:
1
11
2024
pubmed:
1
11
2024
entrez:
1
11
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39482699
doi: 10.1186/s12964-024-01912-3
pii: 10.1186/s12964-024-01912-3
doi:
Substances chimiques
KDM6A protein, human
EC 1.14.11.-
Cisplatin
Q20Q21Q62J
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
Histone Demethylases
EC 1.14.11.-
GSK-J4
0
KDM6B protein, human
EC 1.14.11.-
Benzazepines
0
Polycomb-Group Proteins
0
Pyrimidines
0
Nuclear Proteins
0
Antineoplastic Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
528Subventions
Organisme : NIH HHS
ID : T32ES007326
Pays : United States
Organisme : NIH HHS
ID : CA211875
Pays : United States
Organisme : U.S. Department of Defense
ID : W81XWH2110903
Informations de copyright
© 2024. The Author(s).
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