Circ-ZNF609 regulates G1-S progression in rhabdomyosarcoma

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • RNA / genetics*
  • RNA, Circular
  • Rhabdomyosarcoma / genetics*
  • Rhabdomyosarcoma / immunology
  • Rhabdomyosarcoma / pathology*
  • Rhabdomyosarcoma, Alveolar / genetics
  • Rhabdomyosarcoma, Alveolar / immunology
  • Rhabdomyosarcoma, Alveolar / pathology
  • Rhabdomyosarcoma, Embryonal / genetics
  • Rhabdomyosarcoma, Embryonal / immunology
  • Rhabdomyosarcoma, Embryonal / pathology
  • Up-Regulation


  • RNA, Circular
  • RNA