Universität zu Köln

Richter, Antje M., Kuester, Miriam M., Woods, Michelle L., Walesch, Sara K., Goekyildirim, Mira Y., Krueger, Marcus ORCID: 0000-0003-2008-4582 and Dammann, Reinhard H. (2019). RASSF10 Is a TGF beta-Target That Regulates ASPP2 and E-Cadherin Expression and Acts as Tumor Suppressor That Is Epigenetically Downregulated in Advanced Cancer. Cancers, 11 (12). BASEL: MDPI. ISSN 2072-6694

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Abstract

The Ras Association Domain Family (RASSF) encodes members of tumor suppressor genes which are frequently inactivated in human cancers. Here, the function and the regulation of RASSF10, that contains a RA (Ras-association) and two coiled domains, was investigated. We utilized mass spectrometry and immuno-precipitation to identify interaction partners of RASSF10. Additionally, we analyzed the up- and downstream pathways of RASSF10 that are involved in its tumor suppressive function. We report that RASSF10 binds ASPP1 (Apoptosis-stimulating protein of p53) and ASPP2 through its coiled-coils. Induction of RASSF10 leads to increased protein levels of ASPP2 and acts negatively on cell cycle progression. Interestingly, we found that RASSF10 is a target of the EMT (epithelial mesenchymal transition) driver TGF beta (Transforming growth factor beta) and that negatively associated genes of RASSF10 are significantly over-represented in an EMT gene set collection. We observed a positive correlation of RASSF10 expression and E-cadherin that prevents EMT. Depletion of RASSF10 by CRISPR/Cas9 technology induces the ability of lung cancer cells to proliferate and to invade an extracellular matrix after TGF beta treatment. Additionally, knockdown of RASSF10 or ASPP2 induced constitutive phosphorylation of SMAD2 (Smad family member 2). Moreover, we found that epigenetic reduction of RASSF10 levels correlates with tumor progression and poor survival in human cancers. Our study indicates that RASSF10 acts a TGF beta target gene and negatively regulates cell growth and invasion through ASPP2. This data suggests that epigenetic loss of RASSF10 contributes to tumorigenesis by promoting EMT induced by TGF beta.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Richter, Antje M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuester, Miriam M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Woods, Michelle L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Walesch, Sara K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goekyildirim, Mira Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED orcid.org/0000-0003-2008-4582 UNSPECIFIED Dammann, Reinhard H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-125418
DOI:	10.3390/cancers11121976
Journal or Publication Title:	Cancers
Volume:	11
Number:	12
Date:	2019
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA METHYLATION; MESENCHYMAL TRANSITION; TRANSCRIPTION FACTOR; CELL POLARITY; FAMILY; GENE; INACTIVATION; MECHANISMS; RAS; ASSOCIATION Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12541