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Cell Res. 2019 Aug;29(8):628-640. doi: 10.1038/s41422-019-0192-1. Epub 2019 Jun 17.

Intragenic antagonistic roles of protein and circRNA in tumorigenesis.

Author information

1
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
2
Cedars-Sinai Medical Center, Department of Radiation Oncology, Samuel Oschin Comprehensive Cancer Center, Los Angeles, CA, 90048, USA.
3
Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, Newark, NJ, 07103, USA.
4
Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark; Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.
5
MGH Center for Sarcoma and Connective Tissue Oncology, Department of Orthopedic Surgery, New York, USA.
6
MGH Center for Sarcoma and Connective Tissue Oncology, Department of Pathology, New York, USA.
7
Department of Pathology, Mount Sinai School of Medicine, The Mount Sinai Medical Center, New York, NY, 10029, USA.
8
Department of Medical and Molecular Sciences, University of Delaware, Newark, DE, 19716, USA.
9
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. ppandolf@bidmc.harvard.edu.

Abstract

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.

PMID:
31209250
PMCID:
PMC6796857
[Available on 2020-08-01]
DOI:
10.1038/s41422-019-0192-1

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