Melatonin and Hippo Pathway: Is There Existing Cross-Talk?

Abstract

Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading to several cellular signaling cascades. Recently, the involvement of melatonin in cancer insurgence and progression has clearly been demonstrated. In this review, we will first describe the structure and functions of melatonin and its receptors, and then discuss both molecular and epidemiological evidence on melatonin anticancer effects. Finally, we will shed light on potential cross-talk between melatonin signaling and the Hippo signaling pathway, along with the possible implications for cancer therapy.

Keywords: GPCR signaling; Hippo pathway; cancer; melatonin; melatonin receptors.

Figure 1

Oncosuppressive mechanisms mediated by melatonin. Melatonin (MLT) signaling has been shown to reduce the abundance and transcriptional activity of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) transcription factor as well as to activate phosphorylation cascades mediated by mitogen-activated protein kinases (MAPKs) such as MEK1/2, ERK1/2, JNK, and p38. Both NF-κB inhibition and MAPKs activation in turn inhibit cell growth and motility, and promote apoptosis and DNA damage repair through mechanisms involving the accumulation of oncosuppressors such as p53, p27^kip1, and p21, activation of DNA repair complexes such as P53/PML/H2AX on DNA damage sites, and transcriptional control of genes involved in the cell cycle, apoptosis, and invasiveness. Even though it is still a matter of debate, there is the possibility that melatonin can also bind to nuclear receptors RZR/ROR, controlling the transcription of RORE (ROR response Elements) on genes of the retinoic acid response, among which are several genes controlling cell cycle progression and cell growth (p21, 5-lipoxygenase, and others). Finally, melatonin can bind to the intracellular protein calmodulin (CaM) and reduce the Estrogen Receptor α (ERα) response in ER positive cells by impairing the formation of a proper E2–ERα–CaM complex on Estrogen Receptor Elements (EREs) on target genes. Arrows indicate activation, while dashed and blunt lines indicate inhibition. Activation indicates an increase in protein or activity levels, while inhibition indicates a decrease in protein or activity levels.

Figure 2

Interplay between G-Protein Coupled Receptors (GPCR) signaling regulated by melatonin and GPCR signaling regulating YAP/TAZ. MT1 binding by melatonin (MLT) induces activation of associated Gαq and Gαs that leads to the accumulation of intracellular cAMP that in turn activates Protein Kinase A (PKA) and PKC. These in turn inhibit NF-κB transcriptional activity on its target promoters, including TAZ promoter. In Androgen Receptor (AR) positive cells, PKA and PKC inhibit the androgen response on AR responsive genes. In parallel, glucagon, epinephrine, and dobutamine signal through Gαs, inducing increased intracellular cAMP and activation of PKA. This in turn inhibits the RhoGTPase RhoA and activates LATS1/2 kinases, resulting in phosphorylation of YAP/TAZ, their cytoplasmic sequestration by 14-3-3 protein, their degradation mediated by βTrCP, and the impairment of their nuclear activity on pro-proliferative, pro-metastatic, and anti-apoptotic genes. ↑ indicates an increase in protein levels or activity; ↓ indicates a decrease in protein levels or activity.

Figure 3

Interplay between melatonin, YAP/TAZ, and metabolic pathways. Melatonin (MLT) upregulates glucagon production and downregulates insulin production and signaling. Glucagon inhibits YAP/TAZ nuclear function through Gαs signaling. Conversely, insulin and GPCR signaling synergize to positively regulate nuclear YAP onto YAP/TEAD target genes. In addition, YAP/TAZ activate AKT and mTOR, which are part of the insulin signaling. In conclusion, melatonin may inhibit YAP/TAZ nuclear function by inducing glucagon expression and decreasing insulin expression. On the other hand, YAP/TAZ positively regulate insulin signaling, and, vice versa, insulin signaling positively regulates YAP, suggesting an antagonism between melatonin function and nuclear YAP/TAZ function. Arrows indicate activation, while dashed and blunt lines indicate inhibition. The figure also shows the interaction between the insulin receptor scaffold 4 (IRS4) with insulin receptor, integrins, and MT1/2 receptors potentially linking these transmembrane proteins at the cell membrane. IR = Insulin Receptor, IRS1/2/4 = insulin receptor scaffold 1/2/4.

Figure 4

Interplay between melatonin signaling, cell contact-cell polarity complexes, mechanotransduction, and YAP/TAZ. Melatonin signaling inhibits RhoA/ROCK and increases the expression of cell surface adhesion molecules such as E-cadherin. This suggests that it may inhibit YAP/TAZ nuclear function, which in turn is promoted by RhoA/ROCK and inhibited by cell adhesion molecules. P120 catenin has been co-purified with MT1/MT2 receptors. When localized at the plasma membrane, it stabilizes E-cadherin at the adherens junction (AJ) while inhibiting RhoA–ROCK, thus inhibiting nuclear YAP/TAZ (Y/T). MT1/2 also co-purified with MUPP1 scaffold protein, which interacts with ZO-1 at tight junctions (TJ). Moreover, several studies showed that ZO-1 binds Gα proteins. This suggests a possible interaction with TAZ, which has been demonstrated to be sequestered at the plasma membrane through its interaction with ZO-1 at tight junctions. Moreover, YAP/TAZ may be sequestered at the plasma membrane by the 14-3-3 protein, which has been co-purified with MT1 and MT2. MT1/2 have also been co-purified with filaminA, involved in mechanotransdution, suggesting a link between melatonin receptor signaling and mechanotransduction, which has been demonstrated to regulate YAP/TAZ function and to be in turn controlled by YAP/TAZ. Finally, YAP has been co-purified with NOS1AP (nitric oxide synthase1 adaptor protein) in the complex formed with the scribble polarity proteins in proximity to cell–cell contacts. As NOS (nitric oxid syntase) has been co-purified with MT1/MT2, this again may suggest a possible indirect interaction of YAP with MT1/MT2 at the plasma membrane. In general, YAP/TAZ sequestration at the plasma membrane prevents their nuclear pro-proliferative function. Arrows indicate activation, while dashed and blunt lines indicate inhibition.