Abstract
The Hippo pathway regulates organ size, growth and comprises several tumor related factors, including the oncoprotein YAP1 and the tumor suppressor RASSF1A. RASSF1A is frequently epigenetically inactivated in cancer. In our study, we analyzed the effect of RASSF1A on the function of YAP1. Expression of YAP1 resulted in the downregulation of several tumor suppressor genes and induction of S-phase. Co-expression with RASSF1A normalized the expression levels of these tumor suppressors and induced a G0-G1 arrest and apoptosis. This effect was associated with the reduction of MDM2 and the increase of p53. These data suggest that the tumor suppressor RASSF1A inhibits the oncogenic potential of YAP1. Additionally, we could show that ANKRD1 is a YAP1 target gene that is induced by RASSF1A. Further analysis revealed that ANKRD1 is epigenetically inactivated in human cancer. ANKRD1 expression induced the expression of TP53 as well as BAX and CDKN1A and reduced colony formation of cancer cells. We found that ANKRD1 interacts with p53 and is involved in the destabilization of MDM2. Additionally, our data indicate that the tumor-suppressive effect of ANKRD1 depends on the presence of p53. These results suggest that ANKRD1 is a tumor-suppressive downstream target of the Hippo pathway that is epigenetically silenced in human cancer.
Highlights
The Hippo pathway is a kinase cascade that regulates the organ size and plays an important role in cell differentiation, proliferation and cell death [1]
YAP1 induction resulted in significantly lower RASSF1A (48%) and TP53 (29%) expression levels compared to untreated cells (Figure 1B)
The inactivation or activation of key regulators leads to an imbalance in this pathway, which may alter the pro-apoptotic effect of the Hippo pathway by switching it into the oncogenic function [43]
Summary
The Hippo pathway is a kinase cascade that regulates the organ size and plays an important role in cell differentiation, proliferation and cell death [1]. In this pathway, the tumor suppressor RASSF1A activates the mammalian STE20 like kinases 1 and 2 (MST1/ MST2) via its Salvador/RASSF/Hippo domain [2, 3]. Depending on the cellular context, YAP1 acts as a co-activator of transcription factors such as TEAD [8], SMAD [9] or TP73 [10] to regulate the expression of target genes that are involved in cell proliferation or apoptosis. The tumor-related functions of YAP1 may depend on different upstream activators and/ or transcriptional co-factors resulting in the activation of distinct target genes [1, 5, 29, 30]
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