Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type
Summary: 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...
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Elsevier
2025-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422500029X |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jessica D. Lang |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-45ad8026c1cf431d96f1d7d4cbb6ee52 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-45ad8026c1cf431d96f1d7d4cbb6ee522025-01-23T05:27:36ZengElsevieriScience2589-00422025-02-01282111770Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic typeJessica D. Lang0William Selleck1Shawn Striker2Nicolle A. Hipschman3Rochelle Kofman4Anthony N. Karnezis5Felix K.F. Kommoss6Friedrich Kommoss7Jae Rim Wendt8Salvatore J. Facista9William P.D. Hendricks10Krystal A. Orlando11Patrick Pirrotte12Elizabeth A. Raupach13Victoria L. Zismann14Yemin Wang15David G. Huntsman16Bernard E. Weissman17Jeffrey M. Trent18Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA; 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; Corresponding authorDivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADepartment of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USAInstitute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, GermanyInstitute of Pathology, Medizin Campus Bodensee, 88048 Friedrichshafen, GermanyDepartment of Pathology and Laboratory Medicine, UW Carbone Cancer Center, and Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, WI 53705, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADepartment of Pathology and Laboratory Medicine, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USACollaborative Center for Translational Mass Spectrometry, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; Canada and Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 0B4, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; Canada and Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 0B4, Canada; Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaDepartment of Pathology and Laboratory Medicine, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USADivision of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USASummary: 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.http://www.sciencedirect.com/science/article/pii/S258900422500029XMolecular biologyComplex system biologyCancer |
| spellingShingle | 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 Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type iScience Molecular biology Complex system biology Cancer |
| title | Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type |
| title_full | Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type |
| title_fullStr | Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type |
| title_full_unstemmed | Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type |
| title_short | Super-enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type |
| title_sort | super enhancers and efficacy of triptolide in small cell carcinoma of the ovary hypercalcemic type |
| topic | Molecular biology Complex system biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S258900422500029X |
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