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
Affiliations
Jessica D. Lang
Division 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 author
William Selleck
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Shawn Striker
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Nicolle A. Hipschman
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Rochelle Kofman
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Anthony N. Karnezis
Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA 95817, USA
Felix K.F. Kommoss
Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
Friedrich Kommoss
Institute of Pathology, Medizin Campus Bodensee, 88048 Friedrichshafen, Germany
Jae Rim Wendt
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
Salvatore J. Facista
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
William P.D. Hendricks
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Krystal A. Orlando
Department of Pathology and Laboratory Medicine, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
Patrick Pirrotte
Collaborative Center for Translational Mass Spectrometry, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Elizabeth A. Raupach
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Victoria L. Zismann
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Yemin Wang
Department 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
David G. Huntsman
Department 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, Canada
Bernard E. Weissman
Department of Pathology and Laboratory Medicine, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
Jeffrey M. Trent
Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
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.
