Abstract
Simple SummaryIn 2020, the global cancer database GLOBOCAN estimated 19.3 million new cancer cases worldwide. The discovery of targeted therapies may help prognosis and outcome of the patients affected, but the understanding of the plethora of highly interconnected pathways that modulate cell transformation, proliferation, invasion, migration and survival remains an ambitious goal. Here we propose an updated state of the art of YAP as the key protein driving oncogenic response via promoting all those steps at multiple levels. Of interest, the role of YAP in immunosuppression is a field of evolving research and growing interest and this summary about the current pharmacological therapies impacting YAP serves as starting point for future studies.Yes-associated protein (YAP) has emerged as a key component in cancer signaling and is considered a potent oncogene. As such, nuclear YAP participates in complex and only partially understood molecular cascades that are responsible for the oncogenic response by regulating multiple processes, including cell transformation, tumor growth, migration, and metastasis, and by acting as an important mediator of immune and cancer cell interactions. YAP is finely regulated at multiple levels, and its localization in cells in terms of cytoplasm–nucleus shuttling (and vice versa) sheds light on interesting novel anticancer treatment opportunities and putative unconventional functions of the protein when retained in the cytosol. This review aims to summarize and present the state of the art knowledge about the role of YAP in cancer signaling, first focusing on how YAP differs from WW domain-containing transcription regulator 1 (WWTR1, also named as TAZ) and which upstream factors regulate it; then, this review focuses on the role of YAP in different cancer stages and in the crosstalk between immune and cancer cells as well as growing translational strategies derived from its inhibitory and synergistic effects with existing chemo-, immuno- and radiotherapies.
Highlights
Yes-associated protein (YAP) has emerged as a key component in cancer signaling and is considered a potent oncogene
The nucleus itself might be considered a mechanotransducer for YAP regulation; forces applied to the nucleus are sufficient to represent a signal for YAP nuclear translocation and for the reduction of the mechanical resistance of pores localized on its membrane [48] (Figure 1)
The last modulator of YAP signaling involved in cell polarity is Merlin and its adaptor protein Na+ /H+ exchanger regulatory factor (NHERF); Merlin is localized in the inner portion of the plasma membrane (PM) and constitutes a bridge linking adherens junctions to the kinase module of the Hippo pathway, and it is able to recruit and stabilize LATS1-2
Summary
YAP undergoes constant and rapid phosphorylation and dephosphorylation in response to a multitude of intrinsic and extrinsic signals but not always in a Hippo-dependent manner [5]. These multiple signaling cascades may act in parallel, cooperate to reach stronger responses, or contrast with each other [32]. We can mention at least four large groups of upstream pathways that regulate. YAP nuclear localization and function [33], subdivided into: (i) mechanotransduction; (ii) polarity and tight junction proteins; (iii) the cadherin-catenin complex; and (iv) soluble growth factors
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