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Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type

Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare ovarian cancer affecting young females and is driven by the loss of both SWI/SNF ATPases SMARCA4 and SMARCA2. As loss of SWI/SNF alters enhancers, we hypothesized that super-enhancers, which regulate oncogene expression in cance...

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Hauptverfasser: Lang, Jessica (VerfasserIn) , Selleck, William (VerfasserIn) , Striker, Shawn (VerfasserIn) , Hipschman, Nicolle A. (VerfasserIn) , Kofman, Rochelle (VerfasserIn) , Karnezis, Anthony N. (VerfasserIn) , Kommoss, Felix (VerfasserIn) , Kommoss, Friedrich (VerfasserIn) , Wendt, Jae Rim (VerfasserIn) , Facista, Salvatore J. (VerfasserIn) , Hendricks, William P. D. (VerfasserIn) , Orlando, Krystal A. (VerfasserIn) , Pirrotte, Patrick (VerfasserIn) , Raupach, Elizabeth A. (VerfasserIn) , Zismann, Victoria L. (VerfasserIn) , Wang, Yemin (VerfasserIn) , Huntsman, David G. (VerfasserIn) , Weissman, Bernard E. (VerfasserIn) , Trent, Jeffrey M. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: January 7, 2025
In: iScience
Year: 2025, Jahrgang: 28, Heft: 2, Pages: 1-e6
ISSN:2589-0042
DOI:10.1016/j.isci.2025.111770
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.isci.2025.111770
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S258900422500029X
Volltext
Verfasserangaben:Jessica D. Lang, William Selleck, Shawn Striker, Nicolle A. Hipschman, Rochelle Kofman, Anthony N. Karnezis, Felix K.F. Kommoss, Friedrich Kommoss, Jae Rim Wendt, Salvatore J. Facista, William P.D. Hendricks, Krystal A. Orlando, Patrick Pirrotte, Elizabeth A. Raupach, Victoria L. Zismann, Yemin Wang, David G. Huntsman, Bernard E. Weissman, and Jeffrey M. Trent
Beschreibung
Zusammenfassung:Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare ovarian cancer affecting young females and is driven by the loss of both SWI/SNF ATPases SMARCA4 and SMARCA2. As loss of SWI/SNF alters enhancers, we hypothesized that super-enhancers, which regulate oncogene expression in cancer, are disparately impacted by SWI/SNF loss. We discovered differences between SWI/SNF occupancy at enhancers vs. super-enhancers. SCCOHT super-enhancer target genes were enriched in developmental processes, most notably nervous system development. This may further support neuronal cell-of-origin previously proposed. We found high sensitivity of SCCOHT cell lines to triptolide. Triptolide inhibits expression of many super-enhancer-associated genes, including oncogenes. SALL4 expression is decreased by triptolide and is highly expressed in SCCOHT tumors. In patient-derived xenograft models, triptolide and prodrug minnelide effectively inhibit tumor growth. These results reveal unique features of super-enhancers in SCCOHT, which may be one mechanism through which triptolide has high activity in these tumors.
Beschreibung:Gesehen am 29.09.2025
Beschreibung:Online Resource
ISSN:2589-0042
DOI:10.1016/j.isci.2025.111770

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