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Volume 29, No 8, Aug 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 8, August 2019: 628-640

ORIGINAL ARTICLES

Intragenic antagonistic roles of protein and circRNA in tumorigenesis

Jlenia Guarnerio 1,8, Yang Zhang1, Giulia Cheloni1, Riccardo Panella1, Jesse Mae Katon1, Mark Simpson2, Akinobu Matsumoto1,Antonella Papa 1, Cristian Loretelli1, Andreas Petri3, Sakari Kauppinen3, Cassandra Garbutt4, Gunnlaugur Petur Nielsen5,Vikram Deshpande5, Mireia Castillo-Martin6, Carlos Cordon-Cardo6, Spentzos Dimitrios4, John G. Clohessy 1, Mona Batish 2,7 and Pier Paolo Pandolfi 1

1Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; 2Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, Newark, NJ 07103, USA; 3Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; 4MGH Center for Sarcoma and Connective Tissue Oncology, Department of Orthopedic Surgery, New York, USA; 5MGH Center for Sarcoma and Connective Tissue Oncology, Department of Pathology, New York, USA; 6Department of Pathology, Mount Sinai School of Medicine, The Mount Sinai Medical Center, New York, NY 10029, USA and 7Department of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716, USA
 Correspondence: Pier Paolo Pandolfi (ppandolf@bidmc.harvard.edu) 8Present address: Cedars-Sinai Medical Center, Department of Radiation Oncology, Samuel Oschin Comprehensive Cancer Center, Los Angeles, CA 90048, USAThese authors contributed equally: Yang Zhang, G

circRNAs arise from back splicing events during mRNA processing, and when deregulated can play an active role in cancer. Here we characterize a new circRNA (circPOK) encoded by the Zbtb7a gene (also kown as POKEMON, LRF) in the context of mesenchymal tumor progression. circPOK functions as a non-coding proto-oncogenic RNA independently and antithetically to its linear transcript counterpart, which acts as a tumor suppressor by encoding the Pokemon transcription factor. We find that circPOK regulates pro-proliferative and pro-angiogenic factors by co-activation of the ILF2/3 complex. Importantly, the expression of Pokemon protein and circRNA is aberrantly uncoupled in cancer through differential post-transcriptional regulation. Thus, we identify a novel type of genetic unit, the iRegulon, that yields biochemically distinct RNA products, circular and linear, with diverse and antithetical functions. Our findings further expand the cellular repertoire towards the control of normal biological outputs, while aberrant expression of such components may underlie disease pathogenesis including cancer.


https://doi.org/10.1038/s41422-019-0192-1

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