RASSF1A Tumour Suppressor: Target the Network for Effective Cancer Therapy

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.

IQGAP1 Is a Scaffold of the Core Proteins of the Hippo Pathway and Negatively Regulates the Pro-Apoptotic Signal Mediated by This Pathway

“…Thus, the IQ domains of IQGAP1 seem to mediate the interaction of different kinase cassettes. Of note, the observation that LATS1, YAP and MST2 bind to the same domains of IQGAP1 where RAF and MEK bind indicates that this scaffold might be important for the regulation of the crosstalk between these two pathways [ 1 , 4 , 9 , 42 , 43 ], which should be further explore in the future.…”

“…Inhibition of the core kinases results in YAP1 translocation to the nucleus, where it binds the transcription factor TEAD and mediates the activation of the pro-survival transcriptional program. On the other hand, the role of the RASSF family seems to be more complex, as these proteins induce different cell fates [ 8 , 9 ]. The tumour suppressor RASSF1A, one of the most commonly deregulated genes in cancer, also scaffolds the interaction of MST2 and LATS1 and promotes the activation of these kinases [ 5 , 10 , 11 ].…”

Could the methylation of RASSF1A be the potential epigenetic biomarker for nasopharyngeal carcinoma? – Systematic review and meta-analysis

“…RASSF1A (RAS-association domain family 1 isoform A), located 3p21.31, belonged to the family of RAS effectors, is the well described tumor suppressor gene, encodes the scaffold protein member of the Cterminal RASSF family [16]. It functioned as the signaling protein that plays important roles in cell signal transduction through regulating the complex signal networks, includes ERK, Hippo, apoptotic and p53, death receptor signal pathways [17]. The RASSF1A network modulates different biological functions, includes apoptosis, cell cycle, DNA repair process, migration as well as autography [15][16][17].…”

“…It functioned as the signaling protein that plays important roles in cell signal transduction through regulating the complex signal networks, includes ERK, Hippo, apoptotic and p53, death receptor signal pathways [17]. The RASSF1A network modulates different biological functions, includes apoptosis, cell cycle, DNA repair process, migration as well as autography [15][16][17]. The hypermethylation of two CpG islands located at RASSF1A gene' promoter mediated by DNA methyltransferase (DNMT), includes DNMT1, DNMT3A-3B, results in its loss of expression [17,18].…”

“…The RASSF1A network modulates different biological functions, includes apoptosis, cell cycle, DNA repair process, migration as well as autography [15][16][17]. The hypermethylation of two CpG islands located at RASSF1A gene' promoter mediated by DNA methyltransferase (DNMT), includes DNMT1, DNMT3A-3B, results in its loss of expression [17,18]. Increasing evidences demonstrated this aberrant hypermethylation is one of the most common events in human diseases, includes NPC, through the deregulation of its complex signal networks, and it is thought to be necessary for the development of disease.…”