The tumor suppressor RASSF1A induces the YAP1 target gene ANKRD1 that is epigenetically inactivated in human cancers and inhibits tumor growth
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Adriana P. Jiménez1, Annalena Traum1, Thomas Boettger2, Holger Hackstein3, Antje M. Richter1 and Reinhard H. Dammann1,4
1Institute for Genetics, Justus-Liebig University Giessen, D-35392 Giessen, Germany
2Department I-Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany
3Clinical Immunology, Biomedizinisches Forschungszentrum Seltersberg, D-35392 Giessen, Germany
4German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, D-35392 Giessen, Germany
Reinhard H. Dammann, email: firstname.lastname@example.org
Keywords: RASSF1, YAP1, ANKRD1, tumor suppressor gene, epigenetic
Received: June 07, 2016 Accepted: May 12, 2017 Published: May 23, 2017
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.
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