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Oncogene. 2019 May;38(20):3843-3854. doi: 10.1038/s41388-019-0699-4. Epub 2019 Jan 22.

Circ-ZNF609 regulates G1-S progression in rhabdomyosarcoma.

Author information

1
Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy.
2
Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
3
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
4
Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy. irene.bozzoni@uniroma1.it.
5
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy. irene.bozzoni@uniroma1.it.

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.

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