Argonaute Proteins Take Center Stage in Cancers

Abstract

Argonaute proteins (AGOs) play crucial roles in RNA-induced silencing complex (RISC) formation and activity. AGOs loaded with small RNA molecules (miRNA or siRNA) either catalyze endoribonucleolytic cleavage of target RNAs or recruit factors responsible for translational silencing and target destabilization. miRNAs are well characterized and broadly studied in tumorigenesis; nevertheless, the functions of the AGOs in cancers have lagged behind. Here, we discuss the current state of knowledge on the role of AGOs in tumorigenesis, highlighting canonical and non-canonical functions of AGOs in cancer cells, as well as the biomarker potential of AGO expression in different of tumor types. Furthermore, we point to the possible application of the AGOs in development of novel therapeutic approaches.

Keywords: Argonaute; biomarker; cancer; miRNA; therapeutics; tumorigenesis.

Figure 1

Argonaute (AGO) related research. (a) The total number and (b) the number of cancer-related studies of AGO1–4 found in PubMed using keywords “AGO1/AGO2/AGO3/AGO4” and “cancer”, until 13 January 13 2021. (c) Highlighted studies that show the detailed molecular mechanisms of AGO1–4 in cancer-related processes, based on ref [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. Created with BioRender.com (accessed date: 21 January 2021).

Figure 2

Graphical depiction of AGO-regulated tumor associated processes. (a) AGO4 enhances miRNA methylation, which inhibits miRNA activity [38]; (b) mutated KRAS protein negatively regulates AGO2 activity [28,29]; (c) AGO proteins mediate RNAi in cytoplasm [1] and (d) nucleus [47] in cancer cells; (e) AGO1 and AGO2 bind to promoters of oncogenes to activate transcription [18,19,20]; (f) AGO1 translational read-through variant, AGO1x, inhibits interferon-induced apoptosis via the depletion of nuclear dsRNA [22]; (g) AGO2 recruits RAD51, MMSET and KAT5 proteins to dsDNA breaks to facilitate DNA repair [33,34]; (h) AGO2 promotes telomerase activity [37]; (i) AGO2 tethers MYC mRNA and increases its stability [27]; (j) AGO2 activity is regulated via ERβ [31]. Created with BioRender.com (accessed date: 21 January 2021).

Figure 3

(a–k) Dysregulation of AGO1–4 in cancers, based on refs [7,95,96,97,98,99,100,101,102,103,104,105,106,107,108]. Created with BioRender.com (accessed date: 21 January 2021).