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Rnd3 in Cancer: a Review of the Evidence for Tumor Promoter Or Suppressor Lisa Paysan1,2,Leo Piquet1,2,Fred Eric Saltel1,2, and Violaine Moreau1,2

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Rnd3 in Cancer: a Review of the Evidence for Tumor Promoter Or Suppressor Lisa Paysan1,2,Leo� Piquet1,2,Fred� Eric� Saltel1,2, and Violaine Moreau1,2 Published OnlineFirst August 23, 2016; DOI: 10.1158/1541-7786.MCR-16-0164 Review Molecular Cancer Research Rnd3 in Cancer: A Review of the Evidence for Tumor Promoter or Suppressor Lisa Paysan1,2,Leo Piquet1,2,Fred eric Saltel1,2, and Violaine Moreau1,2 Abstract Rho-GTPases are members of the Ras superfamily of small squamous cell carcinoma. Although there appears to be no GTPases and are general modulators of important cellular general consensus about Rnd3 expressionincancersasthis processes in tumor biology such as migration and proliferation. protein is differently altered according to the tumor context, Among these proteins, Rnd3/RhoE, an atypical Rho-GTPase these alterations overwhelmingly favor a protumorigenic role. devoid of GTP hydrolytic activity, has recently been studied for Thus, depending on the tumor type, it may behave either as a its putative role in tumorigenesis. Indeed, Rnd3 is implicated in tumor suppressor or as a tumor promoter. Importantly, the processes, such as proliferation and migration, whose deregu- deregulation of Rnd3, in most cases, is linked to patient poor lation is linked to cancer development and metastasis. The aim outcome. of this review is to provide an overview of the data surrounding Rnd3 deregulation in cancers, its origin, and consequences. Implications: Rnd3 has prognostic marker potential as exem- Presented here is a comprehensive account of the expression plified in lung cancers and Rnd3 or Rnd3-associated sig- status and biological output obtained in prostate, liver, stom- naling pathways may represent a new putative therapeutic ach, colon, lung, and brain cancers as well as in melanoma and target. Mol Cancer Res; 14(11); 1033–44. Ó2016 AACR. Introduction sequencing of tumors led to the discovery of recurrent muta- tions of Rho-GTPase RHOA and RAC1 genes (5–10). In addi- Small GTP-binding proteins are signaling components that tion, the functions of most Rho-GTPases are perturbed in are important in converting extracellular stimuli into a wide cancers through abnormal expression or altered regulation of range of cellular responses. Rho-GTPases, which are part of the their activities. This is the case of Rnd3/RhoE, an atypical Ras superfamily of GTPases, control cell adhesion, cell-cycle member of the Rho family, which is not, so far, described as progression, cell migration, cell morphogenesis, gene expres- recurrently mutated in tumors, but which expression is altered sion, and actin cytoskeleton dynamics. Therefore, they play in an increasing number of cancers. Puzzlingly, depending on critical roles in tumor biology (1, 2). Rho-GTPases are indeed the cancer type, Rnd3 has been considered either as an onco- important regulators of tumor cell proliferation, survival, and gene or a tumor suppressor. Thus, the aim of this review is to invasion. Rho-GTPases were recently involved in the interac- provide an overview of the data describing the de-regulation of tion of cancer cells with the microenvironment, including Rnd3 in cancers and its consequences. cancer-associated fibroblasts, endothelial, and immune cells (1). In addition, through the regulation of gene expression, Rho-GTPases control angiogenesis, stemness, and immune Rnd3/RhoE, an Atypical Rho-GTPase response. Thus, many of the "hallmarks of cancer" as defined Member by Hanahan and Weinberg (3) are linked to the deregulation of Rho-GTPases (4). Genetic alterations of small GTPases under- Besides the well-known triad, Cdc42, Rac1, and RhoA, the score their important role. However, for a long time, in contrast Rho-GTPase family harbors 20 members. Rnd3/Rho8/RhoE with Ras, no gain- or loss-of-function mutations were found in belongs to the Rnd sub-family that also comprises the closely Rho-GTPases in solid tumors. Recently, large-scale exome related Rnd1/Rho6 and Rnd2/Rho7/RhoN proteins, which share 54% to 63% identity pairwise (11). Evolutionary history of the Rho family revealed that Rnd members emerged in chordates, suggesting that they evolved relatively recently 1INSERM, UMR1053 Bordeaux Research in Translational Oncology, (12). Rnd proteins are atypical Rho-GTPases compared to their BaRITOn, Bordeaux, France. 2Univ. Bordeaux, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, Bordeaux, France. typical partners in terms of the proteins' structures and func- tions (13). First, Rnd1 and Rnd3 have N- and C-terminal L. Paysan and L. Piquet contributed equally to this article. extensions of about 30 amino acids relative to Cdc42 (ref. 11; Corresponding Author: Violaine Moreau, INSERM, 146 Rue Leo Saignat, Bor- Fig. 1). Then, unlike the best-characterized Rho family deaux 33076, France. Phone: 33 (0) 5 57 57 12 72; Fax: 33 (0) 5 56 51 40 77; members that are posttranslationally modified by addition E-mail: [email protected] of a geranyl-geranyl group (20 carbons lipid motif) at the doi: 10.1158/1541-7786.MCR-16-0164 C-terminal CAAX (C ¼ Cys, A ¼ aliphatic, X ¼ any amino Ó2016 American Association for Cancer Research. acid) tetrapeptide motif, Rnd proteins are predominantly www.aacrjournals.org 1033 Downloaded from mcr.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 23, 2016; DOI: 10.1158/1541-7786.MCR-16-0164 Paysan et al. Nucleotide Effector binding Domain RhoA Rac1 Cdc42 Rnd1 Rnd2 Rnd3 Nucleotide binding RhoA Rac1 Cdc42 Rnd1 Rnd2 Rnd3 Nucleotide binding RhoA Rac1 Cdc42 Rnd1 Rnd2 Rnd3 CAAX box RhoA Rac1 Cdc42 Rnd1 Rnd2 Rnd3 Figure 1. Alignment of Rnd1, 2, and 3 compared with RhoA, Rac1, and Cdc42. The regions binding the guanine nucleotide, the region considered as the effector binding site, and the C-terminal motif for prenylation (CAAX) are boxed. Stars over the sequence indicate the positions corresponding to key amino acids required for GTP hydrolysis. These data are available from the Protein NCBI database under accession numbers NP_001655 (RhoA), NP_008839 (Rac1),NP_001034891(Cdc42),NP_055285 (Rnd1), NP_005431 (Rnd2), and NP_005159 (Rnd3/RhoE). The amino acid sequences of human Rho-GTPases were aligned using the Kalign (2.0) program for the CLUSTAL multiple sequence alignment. farnesylated (15 carbons lipid motif). Finally, unlike canonical Indeed, Rnd3 was also found regulated through interactions members of the Rho family that are regulated by switching with other proteins, such as 14-3-3 (17) or effectors as Syx/ between an inactive GDP-bound and an active GTP-bound PLEKHG5 (18). Despite its atypical regulation, Rnd3 has been form, Rnd proteins are constitutively bound to GTP. Indeed, implicated in functions commonly regulated by Rho-GTPases as these proteins lack the amino acids that are critical for GTP such as the remodeling of the actin cytoskeleton, and in many hydrolysis (Fig. 1), they have no detectable GTPase activity. basic cellular processes such as cell proliferation, differentia- Accordingly, in its basal state Rnd3 is not cytosolic, but is tion, survival, motility, and adhesion (Fig. 2). In human adult, predominantly associated with membranes (14). As a conse- Rnd3 is widely expressed with the lowest expression in brain, quence, regulation of Rnd3 is controlled preferentially by kidney, and pancreas (11, 14). However, it is quite different the balance between transcription/translation and degradation, expression profile among mouse tissues as an enriched expres- and/or by posttranslational modificationssuchasphosphory- sion of Rnd3 was found in lungs and brain (19). The first clues lation, rather than by classical Rho regulators such as guanine for the in vivo function of Rnd3 came with the development of nucleotide exchange factors (GEF), GTPase-activating proteins knockout (KO) mice that lack Rnd3 expression. Rnd3 null mice (GAP), and GDP-dissociation inhibitors (GDI; refs. 15, 16). died either at E11.0 (C57BL/6 background) or shortly after 1034 Mol Cancer Res; 14(11) November 2016 Molecular Cancer Research Downloaded from mcr.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 23, 2016; DOI: 10.1158/1541-7786.MCR-16-0164 Understanding Atypical Rho-GTPase Rnd3/RhoE in Cancer Glucose uptake (Metabolism) Actin cytoskeleton RhoA/ROCK Pl 3-kinase Cell apoptosis and dynamics ROCK survival Figure 2. Tumor functions of Rnd3/RhoE. Rnd3 has been found to regulate different Rnd3/RhoE caspase3, BAX, Rb, cellular processes important for tumor Functions plaloglobin, BCL-2 growth and progression in vitro. Indicated are major proteins RhoA/ROCK implicated in the specific functions. Cyclin B1/CDK2 Cyclin D1/p21 Notch Cell-cycle LIMK/cofilin progression RhoA/ROCK Cell differentiation Cell polarity birth (hybrid 129SvEvBrd and C57BL/6J background) showing mechanisms that, when deregulated, may lead to cancer devel- that, depending of the genetic background, Rnd3 is essential opment or progression. either for embryo or postnatal development (20, 21). In the C57BL/6 background, death of Rnd3 null embryos was attrib- Rnd3/RhoE Expression Is Differently uted to fetal arrhythmias and heart failure (21). Rnd3 haploin- sufficient (Rnd3Æ) mice, which are viable, yet developed dilat- Altered in Cancers ed cardiomyopathy with heart failure, and the study revealed A growing number of studies have described the alteration of that Rnd3 acted as a proangiogenic factor involved in cardiac Rnd3 expression and function in tumors. Interestingly, Rnd3 responsive angiogenesis through HIF1a–VEGFA signaling (22). expression is differentially regulated in various cancers. Indeed, However,
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