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

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; Jeffrey M Trent

doi:10.1016/j.isci.2025.111770

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

iScience. 2025 Jan 7;28(2):111770. doi: 10.1016/j.isci.2025.111770. eCollection 2025 Feb 21.

Authors

Jessica D Lang^{1

2}, William Selleck¹, Shawn Striker¹, Nicolle A Hipschman¹, Rochelle Kofman¹, Anthony N Karnezis³, Felix K F Kommoss⁴, Friedrich Kommoss⁵, Jae Rim Wendt², Salvatore J Facista¹, William P D Hendricks¹, Krystal A Orlando⁶, Patrick Pirrotte⁷, Elizabeth A Raupach¹, Victoria L Zismann¹, Yemin Wang^{8

9}, David G Huntsman^{8

9

10}, Bernard E Weissman⁶, Jeffrey M Trent¹

Affiliations

¹ Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
² Department of Pathology and Laboratory Medicine, UW Carbone Cancer Center, and Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA.
⁴ Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁵ Institute of Pathology, Medizin Campus Bodensee, 88048 Friedrichshafen, Germany.
⁶ Department of Pathology and Laboratory Medicine, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Collaborative Center for Translational Mass Spectrometry, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
⁸ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada.
⁹ Canada and Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 0B4, Canada.
¹⁰ Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Abstract

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.

Keywords: Cancer; Complex system biology; Molecular biology.