FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 08, 2022
- Source ID
- 10.1158/0008-5472.can-22-0671
Entities
People
- Alexander Crane
- Alexandra L. Condurat
- Audrey Baguette
- Cecilia Sousa
- Christof M Kramm
- Claudia L Kleinman
- Dana Novikov
- David S. Ziegler
- David T. W. Jones
- David W. Wu
- Dayle K. Wang
- Elizabeth M. Gonzalez
- Frank Dubois
- François Aguet
- Gad Getz
- Gnana Prakash Balasubramanian
- Henry W Long
- J'ya Hunter
- James M McFarland
- Jayne Vogelzang
- Jeromy J. Digiacomo
- Jessica W Tsai
- Jinghui Zhang
- Keith L Ligon
- Kevin N. Zhou
- Kristine Pelton
- Madison S. Chacon
- Maria Tsoli
- Michaela Nathrath
- Nada Jabado
- Natalie Jager
- Ningxuan Zhou
- Olaf Witt
- Paloma Cejas
- Phonepasong Arounleut
- Pratiti Bandopadhayay
- Rushil Kumbhani
- Sarah E. Dixon-clarke
- Smruti K Patel
- Sophie D. Lu
- Stefan Bielack
- Stefan M. Pfister
- Sudeepa Syamala
- Suzanne J. Baker
- Timothy N. Phoenix
- Uta Dirksen
- Volker Hovestadt
- Xiaolong Chen
- Xin Wei
Organizations
- Brigham and Women's Hospital
- Cancer Institute of New South Wales
- Cincinnati Children's Hospital Medical Center
- Dana–Farber Cancer Institute
- German Cancer Aid
- German Cancer Research Center
- Harvard Medical School
- Jewish General Hospital
- Massachusetts General Hospital
- McGill University
- National Institutes of Health
- St. Jude Children's Research Hospital
- Technical University of Munich
- United States Department of Defense
- University Hospital Heidelberg
- University of Cincinnati
- University of New South Wales
- Universitätsmedizin Göttingen