Circular RNAs in cell cycle regulation: Mechanisms to clinical significance

Abstract

Circular RNAs (circRNAs), a type of non-coding RNA, are single-stranded circularized molecules characterized by high abundance, evolutionary conservation and cell development- and tissue-specific expression. A large body of studies has found that circRNAs exert a wide variety of functions in diverse biological processes, including cell cycle. The cell cycle is controlled by the coordinated activation and deactivation of cell cycle regulators. CircRNAs exert mutifunctional roles by regulating gene expression via various mechanisms. However, the functional relevance of circRNAs and cell cycle regulation largely remains to be elucidated. Herein, we briefly describe the biogenesis and mechanistic models of circRNAs and summarize their functions and mechanisms in the regulation of critical cell cycle modulators, including cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors. Moreover, we highlight the participation of circRNAs in cell cycle-related signalling pathways and the clinical value of circRNAs as promising biomarkers or therapeutic targets in diseases related to cell cycle disorder.

FIGURE 1

The basic molecular mechanisms of circRNAs. A diverse range of mechanisms have been described for circRNA regulation, including (a) epigenetic/transcriptional regulation, (b) splicing regulation, (c) RNA modification, (d) miRNA sponges, (e) binding proteins, (f) encoding peptides and (g) translation brake

FIGURE 2

Mechanisms of action of circRNAs in cell cycle and proliferation. (A) CircRNAs act as molecular sponges to sequester miRNAs. (B) CircRNAs directly interact with RNA‐binding proteins (RBPs). (C) CircRNAs epigenetically mediate transcriptional regulation. (D) CircRNAs mediate translation regulation

FIGURE 3

CircRNA impact cell cycle progression by regulating diverse cell cycle regulators. Several circRNAs control the expression of cyclins/CDKs, CKIs and participate in cell cycle regulation. M, mitotic phase; S, synthesis phase; G, gap phase; G₁, the gap after cell division and before S phase is called the G₁ phase; G₂, the gap after S phase and before the next cell division is called the G₂ phase

FIGURE 4

The potential clinical application of circRNAs. (A) CircRNAs can be detected in tumour biopsies of patients, and are potential diagnostic and prognostic biomarkers. (B) The functional identification of circRNAs has been elucidated in pre‐clinical models. (C) RNA‐based strategy can effectively target circRNAs in the cytoplasm and nucleus. (D) Combination of circRNA targeting and conventional CKIs enhances therapeutic efficacy through diverse delivery tools in vivo