Deregulated cell cycle control: The interplay between non-coding RNAs and cyclin-dependent kinases in tumorigenesis

Abstract

Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that are at the center of cell cycle progression. Dysregulated CDK activity, found in a range of human cancers, leads to uncontrolled cell growth and development. Non-coding RNAs (ncRNAs), which include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are emerging as critical regulators of gene expression and cellular processes, playing an important and often complex role in cancer development and progression. The purpose of this review is to organize knowledge about the interactions of ncRNAs with CDKs, contribution to cancer biology, and to discuss not only the different ways miRNAs target and downregulate CDKs mRNA, leading to inhibition of cell cycle progression and acting as tumor suppressors, but in the case of some miRNAs alter CDK activity as oncogenes by directly upregulating CDK expression or more frequently suppressing the expression of the canonical CDK inhibitors (p21 and p27). Moreover, long non-coding RNAs (lncRNAs) can regulate CDKs through a variety of mechanisms, such as functioning as molecular sponges by absorbing miRNAs that target CDK proteins as miRNA sponges, modulating CDK protein abundance and/or activity indirectly or directly (i.e., the direct interaction with the CDK proteins can potentially invoke an ability to regulate their stability, etc.). Circulating RNAs (circRNAs) also primarily modulate CDK levels and act as inhibitors of the appropriate CDK targeted by a miRNA sponge, potentially through direct interaction with a CDK. Overall, while our understanding of the ncRNA-CDK network is far from complete, the complexities surrounding ncRNA-CDK oncogenic developments and the ability to target these pathways offer significant promise in the harsh realities of cancerogenesis and further therapeutic interventions to fashion more precise cancer therapies that antagonize aberrant cell cycle progression in cancer subtypes.

Keywords: Cancer; Cell cycle; Cyclin-dependent kinase (CDK); Gene regulation; Non-coding RNA (ncRNA); Tumorigenesis.