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cancers Review Argonaute Proteins Take Center Stage in Cancers Iwona Nowak 1,2 and Aishe A. Sarshad 1,2,* 1 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; [email protected] 2 Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden * Correspondence: [email protected] Simple Summary: The dysregulation of RNA interference (RNAi) has often been observed in cancers, where the main focus of research has been on the small RNA molecules directing RNAi. In this review, we focus on the activity of Argonaute proteins, central components of RNAi, in tumorigenesis, and also highlight their potential applications in grading tumors and anti-cancer therapies. 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; miRNA; cancer; tumorigenesis; biomarker; therapeutics Citation: Nowak, I.; Sarshad, A.A. Argonaute Proteins Take Center Stage in Cancers. Cancers 2021, 13, 788. https://doi.org/10.3390/cancers 13040788 1. Introduction RNA interference (RNAi) plays a crucial role in post-transcriptional regulation of gene Academic Editor: Lyndsay Rhodes expression. In mammalian cells, RNAi is mediated by three classes of small RNA (smRNA), approximately 20–25 nt long, endogenous piwiRNA (piRNA), microRNAs (miRNAs) or Received: 21 January 2021 artificial small interfering RNAs (siRNAs). These smRNAs are loaded to a member of Accepted: 10 February 2021 the Argonaute (AGO) protein family, which comprises an AGO subclass (loaded with Published: 13 February 2021 si/miRNA) and PIWI subclass (loaded with piRNA) [1]. Together, they form the core of the RNA-induced silencing complex (RISC) [2]. Since the discovery of RNAi, AGO Publisher’s Note: MDPI stays neutral involvement in RISC assembly and small RNA (smRNA) maturation has been extensively with regard to jurisdictional claims in studied [3]. However, the complex network of AGO–miRNA interactions, promoting published maps and institutional affil- the maturation and function of specific miRNAs, is still largely unexplored. As a core iations. component of the RISC ribonucleoprotein complex, AGO proteins hold a great importance in fine tuning cellular protein and RNA profiles in order to ensure normal development and homeostasis [1]. It is now estimated that approximately 60% of protein coding genes in human cells are controlled in an RNAi-dependent manner [4]. Copyright: © 2021 by the authors. miRNAs are abundantly expressed in all mammalian cell types and at every stage Licensee MDPI, Basel, Switzerland. of development. However, the smRNA profiles greatly differ spatiotemporally, which This article is an open access article is characteristic for each cellular lineage throughout maturation [5]. In such a manner, distributed under the terms and AGO1–4 protein expression is tightly controlled during development. Normally, the AGOs conditions of the Creative Commons are expressed in a tissue-specific manner where, for example, AGO2 is highly expressed in Attribution (CC BY) license (https:// trachea but to a much lesser degree in kidneys [6]. Generally, AGO1 and AGO2 expression creativecommons.org/licenses/by/ is significantly more prominent as compared to the remaining AGO proteins [7,8]; hence, 4.0/). Cancers 2021, 13, 788. https://doi.org/10.3390/cancers13040788 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 788 2 of 18 Cancers 2021, 13, 788 2 of 17 [7,8]; hence, the volume of published data on AGO1 and AGO2 involvement in tumor- the volume of published data on AGO1 and AGO2 involvement in tumorigenesis is igenesis is relatively large compared to AGO3 and AGO4 publications (Figure 1a,b). Fur- relatively large comparedthermore, to the AGO3 ratio and of AGO4different publications AGO protein (Figure levels,1a,b). with Furthermore, the emphasis the on AGO1 and ratio of different AGOAGO2, protein are tightly levels, controlled with the during emphasis early on stages AGO1 of mammalian and AGO2, embryonic are tightly development controlled during[9] early. The stages expression of mammalian of the AGO embryonic proteins changes development along the [9]. development The expression of organs, exem- of the AGO proteinsplified changes by elevation along the of developmentAGO1–4 levels of in organs, the fetal exemplified brain as compared by elevation to adult of tissue [7]. AGO1–4 levels in the fetalThe dysregulation brain as compared of RNAi to processes adult tissue has [ 7significant]. negative impacts on cellular ho- The dysregulationmeostasis of and RNAi has processes frequently has been significant reported in negative neoplasia. impacts miRNAs on are cellular often dysregulated homeostasis and hasin cancers frequently [10–12 been]. In reported fact, it was in neoplasia.reported that miRNAs there is are a global often dysregulateddownregulation of miRNA in cancers [10–12].expression In fact, it in was cancer reported tissues that [12] there. Numerous is a global miRNA downregulation molecules have of miRNA been described as ei- expression in cancerther tissuescancer promoting [12]. Numerous oncogenes, miRNA referred molecules to as oncomiRs, have been or cancer described demoting as tumor sup- either cancer promotingpressors oncogenes,[10–15]. Moreover, referred similarly to as oncomiRs, to normal tissues, or cancer cancers demoting derived tumor from different ori- suppressors [10–15gin].s Moreover, are characterized similarly by tovarious normal miRNA tissues, dysregulations. cancers derived Of note, from miRNAs different exhibiting tu- origins are characterizedmor suppressive by various activity miRNA in one dysregulations. type of cancer may Of note, promote miRNAs development exhibiting of another [16]. tumor suppressive activity in one type of cancer may promote development of another [16]. (a) (b) (c) Mediates oncogenic activity of miR-10a [17] Recruites RNA Polymerase II to promoters of cancer related genes [18-20] Silencing inhibits hepatocellular carcinoma cells growth and migration [21] AGO1 Silences interferon induced apoptosis via scattering of dsRNAs in breast cancer cells [22] Necessary for differentiation of leukaemia cells upon treatment with retinoic acid [23] Represses VEGF expression and vascularization under hypoxic stress [24] Mediates suppressive activity of miR-145-5p [25] Silencing inhibits growth of hypopharyngeal cancer cells [26] Stabilizes MYC mRNA stability [27] Enhances the activity of mutant KRAS protein [28,29] Overexpression results in decreased proliferation and motility of lung cancer cells [30] AGO2 Interacts with ERβ receptor [31] Required for differentiation of leukaemia cells upon treatment with 1,25-dihydroxyvitamin D [32] Recruits Rad51, MMSET and KAT5 to DNA breaks [33,34] Enhances angiogenesis [35,36] Promotes telomerase activity [37] AGO3 Mediates oncogenic activity of miR-10a [17] Facilitates miRNA methylation [38] AGO4 Selectively increased in neuroblastoma differentiating cells [39] Figure 1. Argonaute (AGO) related research. (a) The total number and (b) the number of cancer- Figure 1. Argonaute (AGO) related research. (a) The total number and (b) the number of cancer-related studies of AGO1– 4 foundrelated in PubMed studies using of keywords AGO1–4 found“AGO1/AGO2/AGO3/ in PubMed usingAGO4” keywords and “cancer” “AGO1/AGO2/AGO3/AGO4”, until 13 January 13 2021. (c and) Highlighted studies“cancer”, that showuntil the detailed 13 January molecular 13 2021. mechanisms (c) Highlighted of AGO1 studies–4 in cancer that show-related the processes, detailedmolecular based on ref mech- [17–39]. Cre- ated withanisms BioRender.com of AGO1–4 (access in cancer-relateded date: 21 January processes, 2021) based. on ref [17–39]. Created with BioRender.com (accessed date: 21 January 2021). AGO proteins are viewed as the mediators of miRNA function rather than the star players of RNAi, and therefore, in much of the literature, documenting the impact of RNAi dysregulation in tumorigenesis focuses on miRNAs and not their partner proteins. Never- Cancers 2021, 13, 788 3 of 17 theless, given the crucial importance of RNAi in the maintenance of cellular homeostasis, AGO proteins are inevitably engaged in cancer development and progression. Hence, un- surprisingly, the 2010s brought a substantial number of reports documenting AGO protein function, dysregulated expression, and mutations in cancer cells and tissues (Figure1c). Herein, we provide a scrutinized summary of the relationship between AGO1–4 proteins and tumorigenesis. 2. The Functional Role of AGO Proteins in RISC The AGO subclass includes four members, AGO1–4, each exhibiting high affinity to miRNA molecules and able to form functional RISC complexes [40]. The AGO proteins are characterized
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