Intragenic antagonistic roles of protein and circRNA in tumorigenesis

• Published in: Cell research Vol. 29; no. 8; pp. 628 - 640
• Main Authors: Guarnerio, Jlenia, Zhang, Yang, Cheloni, Giulia, Panella, Riccardo, Mae Katon, Jesse, Simpson, Mark, Matsumoto, Akinobu, Papa, Antonella, Loretelli, Cristian, Petri, Andreas, Kauppinen, Sakari, Garbutt, Cassandra, Nielsen, Gunnlaugur Petur, Deshpande, Vikram, Castillo-Martin, Mireia, Cordon-Cardo, Carlos, Dimitrios, Spentzos, Clohessy, John G., Batish, Mona, Pandolfi, Pier Paolo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2019; Nature Publishing Group
• Subjects: 14/32; 38; 38/77; 631/67/327; 631/67/68; 64/60; 96/31; Alternative Splicing - genetics; Angiogenesis; Animals; Biomedical and Life Sciences; Cancer; Carcinogenesis - genetics; Cell Biology; Cell Line, Tumor; Deregulation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Exons; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Gene regulation; HEK293 Cells; Humans; Life Sciences; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA processing; Non-coding RNA; Pathogenesis; Post-transcription; Proteins; Proto-Oncogenes - genetics; Ribonucleic acid; RNA; RNA, Circular - genetics; RNA, Small Interfering - genetics; Sarcoma - genetics; Sarcoma - pathology; Splicing; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Tumor suppressor genes; Tumorigenesis; Tumors
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/s41422-019-0192-1

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.