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RASSF1A Tumour Suppressor: Target the Network for Effective Cancer

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RASSF1A Tumour Suppressor: Target the Network for Effective Cancer cancers Review RASSF1A Tumour Suppressor: Target the Network for Effective Cancer Therapy 1, 1, 1,2,3 Lucía García-Gutiérrez y, Stephanie McKenna y , Walter Kolch and David Matallanas 1,2,* 1 Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; [email protected] (L.G.-G.); [email protected] (S.M.); [email protected] (W.K.) 2 School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland 3 Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland * Correspondence: [email protected] Equal contribution. y Received: 21 December 2019; Accepted: 14 January 2020; Published: 17 January 2020 Abstract: The RASSF1A tumour suppressor is a scaffold protein that is involved in cell signalling. Increasing evidence shows that this protein sits at the crossroad of a complex signalling network, which includes key regulators of cellular homeostasis, such as Ras, MST2/Hippo, p53, and death receptor pathways. The loss of expression of RASSF1A is one of the most common events in solid tumours and is usually caused by gene silencing through DNA methylation. Thus, re-expression of RASSF1A or therapeutic targeting of effector modules of its complex signalling network, is a promising avenue for treating several tumour types. Here, we review the main modules of the RASSF1A signalling network and the evidence for the effects of network deregulation in different cancer types. In particular, we summarise the epigenetic mechanism that mediates RASSF1A promoter methylation and the Hippo and RAF1 signalling modules. Finally, we discuss different strategies that are described for re-establishing RASSF1A function and how a multitargeting pathway approach selecting druggable nodes in this network could lead to new cancer treatments. Keywords: RASSF1A; tumour suppressor; cancer; therapy; apoptosis and Hippo pathway; DNMTP 1. Introduction RASSF1A, which is a well described tumour suppressor, is one of the most commonly deregulated genes in human cancers [1]. RASSF1A is a scaffold protein member of the C-terminal RASSF family [2] and is encoded by the RASSF1 gene [2,3]. This gene expresses eight isoforms due to alternative splicing, and RASSF1A along with RASSF1C are the most abundantly expressed isoforms. RASSF1A is a signalling hub that plays an important role in signal transduction, where it seems to mediate a complex network that includes the ERK, Hippo, apoptotic and p53 subnetworks [3]. RASSF1A is also a downstream effector of KRAS mediating the antiproliferative signal that is triggered by the activation of this proto-oncogene [4]. The RASSF1A signalling network (SN) can mediate the regulation of different biological functions, such as apoptosis, cell cycle arrest, regulation of the microtubule network, migration, and autophagy [3,5,6]. Unsurprisingly, the deregulation of RASSF1A function results in the development of different pathologies, including cancer and cardiovascular diseases [7]. However, we still have a very patchy picture of the RASSF1A SN (particularly its upstream regulators) and how this tumour suppressor inputs different signals to effector pathways. The study of RASSF1A at the molecular level and the characterisation of the mechanistic properties of its signalling network are complicated by the very nature of scaffold proteins. These proteins do not have enzymatic functions and they exert their biological effect by bringing their effector proteins Cancers 2020, 12, 229; doi:10.3390/cancers12010229 www.mdpi.com/journal/cancers CancersCancers2020 2020, 12, 229 22 of 2222 concentration of signalling nodes, which can accelerate biochemical reactions and also togethercompartmentalise [8,9]. The assemblysignalling of into these specific protein protein complexes complexes increases or subcellular the local concentration localisations. ofImportantly, signalling nodes,under physiological which can accelerate conditions, biochemical scaffold proteins reactions ha andve alsoan optimal compartmentalise concentration signalling of expression, into specific where proteinthe stoichiometry complexes orof subcellularthe substrates localisations. and the scaffold Importantly, lead to under the physiologicalcomplete assembly conditions, of scaffolded scaffold proteinsproteins, have thereby an optimal optimising concentration the biochemical of expression, reaction where rates the between stoichiometry them (Figure of the substrates 1) [9,10]. andThe theexpression scaffold of lead the to scaffold the complete protein assembly below or of above scaffolded this proteins,optimal concentration thereby optimising window the results biochemical in an reactioninhibition rates or suboptimal between them regulation (Figure 1of)[ the9,10 molecular]. The expression reactions of mediated the scaff oldby the protein bound below effectors or above [11]. thisImportantly, optimal concentration changes in expression window results levels inof an the inhibition scaffold orproteins suboptimal are associated regulation with of the pathological molecular reactionsderegulation mediated of signalling by the bound networks effectors in [several11]. Importantly, diseases changes[12]. In inthe expression case of RASSF1A, levels of the the sca ffmostold proteinscommon are mode associated of deregulation with pathological is the loss deregulation of expression of signalling by gene networkspromoter in hypermethylation several diseases [ 12[2].]. InAdditionally, the case of RASSF1A,it is possible the that, most in common several tumours, mode of deregulationRASSF1A is still is the expressed, loss of expression but at suboptimal by gene promoter(due to loss hypermethylation of heterozygosity [ 2of]. the Additionally, 3p21.3 region it is [3]) possible or even that, supra-optimal in several tumours,concentration. RASSF1A In all isof stillthese expressed, scenarios, but the at deregulation suboptimal (dueof RASSF1A to loss of will heterozygosity lead to a defective of the 3p21.3 regulation region of [3 ])its or signal even supra-optimaltransduction network, concentration. which Inseems all of to these be a scenarios,common event the deregulation in cancer development of RASSF1A [13–16]. will lead In tothis a defectivereview, we regulation give an overview of its signal of the transduction current knowle network,dge of which the RASSF1A seems to SN be awith common special event consideration in cancer developmentfor how the different [13–16]. Insubnetworks this review, wemay give contribute an overview to the of tumour the current suppressor knowledge function of the RASSF1Aof RASSF1A. SN withOf note, special we considerationrefer to signalling for how modules the di ffrathererent subnetworksthan classical may effector contribute pathways to the and tumour to the suppressorindividual functionproteins ofin RASSF1A. the network Of note,as nodes we refer in toorder signalling to give modules a systems rather level than description classical e ffforector the pathways SN. We andspecifically to the individual focus on the proteins different in the strategies network that as nodes have inbeen order tested to give in pre-clinical a systems leveland clinical description models for theto rescue SN. We RASSF1A specifically deregulation. focus on the diFinally,fferent we strategies discuss that potential have been therapeutic tested in pre-clinicalstrategies that and may clinical be modelsdeveloped to rescue to target RASSF1A the different deregulation. modules Finally, of the RASSF1A we discuss SN. potential therapeutic strategies that may be developed to target the different modules of the RASSF1A SN. FigureFigure 1.1. RASSF1A signalling is dependent on itsits levellevel ofof expressionexpression andand thethe stoichiometrystoichiometry ofof itsits complexes.complexes. AsAs exemplifiedexemplified by by the the RASSF1A-sca RASSF1A-scaffoldedffolded complex complex (blue (blue and and orange orange boxes), boxes), if there if there is no is RASSF1Ano RASSF1A expression, expression, or sub or sub optimal optimal expression, expression, there there is low is complexlow complex formation formation and theand signal the signal will bewill low be (left);low (left); in the in case the ofcase intermediate of intermediate RASSF1A RASSF1A expression, expression, signal signal will will be high be high (centre), (centre), this isthis the is physiologicalthe physiological range range of expression; of expression; if there if there is too ismuch too much RASSF1A RASSF1A the signal the signal will bewill low be (right).low (right). 2.2. RegulationRegulation ofof thethe RASSF1ARASSF1A ProteinProtein AsAs aa scascaffoldffold protein,protein, thethe RASSF1ARASSF1A functionsfunctions areare mediatedmediated byby protein-proteinprotein-protein interactioninteraction withwith itsits eeffectorsffectors (Figure(Figure1 ).1). Changes Changes in in RASSF1A RASSF1A protein protein expression expression and and post-translational post-translational modifications modifications (PTM)(PTM) aaffectffect thethe formationformation ofof thesethese proteinprotein complexescomplexes andand regulateregulate thethe activationactivation ofof thethe RASSF1ARASSF1A SNSN [[17].17]. 2.1. Epigenetic Regulation of RASSF1A Expression DNA methylation of two CpG islands located at its promoter regulates RASSF1A expression (Figure 2A and recently reviewed by Malpeli et al [18]). This methylation is mediated by DNA Cancers 2020, 12, 229 3 of 22 2.1. Epigenetic Regulation of RASSF1A Expression DNA methylation of two CpG islands located at its promoter regulates RASSF1A expression (Figure2A and recently
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