1. Circ-ZNF609 regulates G1-S progression in rhabdomyosarcoma.
- Author
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Rossi F, Legnini I, Megiorni F, Colantoni A, Santini T, Morlando M, Di Timoteo G, Dattilo D, Dominici C, and Bozzoni I
- Subjects
- Cell Cycle genetics, Cell Line, Tumor, Cell Proliferation genetics, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, RNA, Circular, Rhabdomyosarcoma immunology, Rhabdomyosarcoma, Alveolar genetics, Rhabdomyosarcoma, Alveolar immunology, Rhabdomyosarcoma, Alveolar pathology, Rhabdomyosarcoma, Embryonal genetics, Rhabdomyosarcoma, Embryonal immunology, Rhabdomyosarcoma, Embryonal pathology, Up-Regulation, RNA genetics, Rhabdomyosarcoma genetics, Rhabdomyosarcoma pathology
- Abstract
Circular RNAs (circRNAs) represent a class of covalently closed RNAs, derived from non-canonical splicing events, which are expressed in all eukaryotes and often conserved among different species. We previously showed that the circRNA originating from the ZNF609 locus (circ-ZNF609) acts as a crucial regulator of human primary myoblast growth: indeed, the downregulation of the circRNA, and not of its linear counterpart, strongly reduced the proliferation rate of in vitro cultured myoblasts. To deepen our knowledge about circ-ZNF609 role in cell cycle regulation, we studied its expression and function in rhabdomyosarcoma (RMS), a pediatric skeletal muscle malignancy. We found that circ-ZNF609 is upregulated in biopsies from the two major RMS subtypes, embryonal (ERMS) and alveolar (ARMS). Moreover, we discovered that in an ERMS-derived cell line circ-ZNF609 knock-down induced a specific block at the G1-S transition, a strong decrease of p-Akt protein level and an alteration of the pRb/Rb ratio. Regarding p-Akt, we were able to show that circ-ZNF609 acts by counteracting p-Akt proteasome-dependent degradation, thus working as a new regulator of cell proliferation-related pathways. As opposed to ERMS-derived cells, the circRNA depletion had no cell cycle effects in ARMS-derived cells. Since in these cells the p53 gene resulted downregulated, with a concomitant upregulation of its cell cycle-related target genes, we suggest that this could account for the lack of circ-ZNF609 effect in ARMS.
- Published
- 2019
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