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FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits.
Tsai, Jessica W; Cejas, Paloma; Wang, Dayle K; Patel, Smruti; Wu, David W; Arounleut, Phonepasong; Wei, Xin; Zhou, Ningxuan; Syamala, Sudeepa; Dubois, Frank P B; Crane, Alexander; Pelton, Kristine; Vogelzang, Jayne; Sousa, Cecilia; Baguette, Audrey; Chen, Xiaolong; Condurat, Alexandra L; Dixon-Clarke, Sarah E; Zhou, Kevin N; Lu, Sophie D; Gonzalez, Elizabeth M; Chacon, Madison S; Digiacomo, Jeromy J; Kumbhani, Rushil; Novikov, Dana; Hunter, J'Ya; Tsoli, Maria; Ziegler, David S; Dirksen, Uta; Jager, Natalie; Balasubramanian, Gnana Prakash; Kramm, Christof M; Nathrath, Michaela; Bielack, Stefan; Baker, Suzanne J; Zhang, Jinghui; McFarland, James M; Getz, Gad; Aguet, François; Jabado, Nada; Witt, Olaf; Pfister, Stefan M; Ligon, Keith L; Hovestadt, Volker; Kleinman, Claudia L; Long, Henry; Jones, David T W; Bandopadhayay, Pratiti; Phoenix, Timothy N.
Afiliación
  • Tsai JW; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Cejas P; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
  • Wang DK; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Patel S; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
  • Wu DW; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, Cancer Program, Broad Institute, Cambridge, Massachusetts.
  • Arounleut P; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Wei X; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Zhou N; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
  • Syamala S; Division of Pediatric Neurosurgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
  • Dubois FPB; Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • Crane A; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Pelton K; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
  • Vogelzang J; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
  • Sousa C; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
  • Baguette A; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, Cancer Program, Broad Institute, Cambridge, Massachusetts.
  • Chen X; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
  • Condurat AL; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, Cancer Program, Broad Institute, Cambridge, Massachusetts.
  • Dixon-Clarke SE; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Zhou KN; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Lu SD; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Gonzalez EM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Chacon MS; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Digiacomo JJ; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Kumbhani R; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Novikov D; Quantitative Life Sciences, McGill University, Montreal, Quebec H3A 2A7, Canada.
  • Hunter J; Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
  • Tsoli M; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Ziegler DS; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Dirksen U; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Jager N; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Balasubramanian GP; Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts.
  • Kramm CM; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Nathrath M; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Bielack S; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Baker SJ; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Zhang J; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • McFarland JM; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Getz G; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Aguet F; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Jabado N; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Witt O; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Pfister SM; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Ligon KL; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Hovestadt V; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Kleinman CL; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Long H; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Jones DTW; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
  • Bandopadhayay P; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
  • Phoenix TN; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Cancer Res ; 82(17): 2980-3001, 2022 09 02.
Article en En | MEDLINE | ID: mdl-35802025
Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis. SIGNIFICANCE: This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Factores de Transcripción Forkhead / Neoplasias Tipo de estudio: Prognostic_studies Límite: Adult / Child / Humans / Male Idioma: En Revista: Cancer Res Año: 2022 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Factores de Transcripción Forkhead / Neoplasias Tipo de estudio: Prognostic_studies Límite: Adult / Child / Humans / Male Idioma: En Revista: Cancer Res Año: 2022 Tipo del documento: Article