Universität zu Köln

Franz, Henriette ORCID: 0000-0001-9358-7442, Greschik, Holger, Willmann, Dominica, Ozretic, Luka, Jilg, Cordula Annette, Wardelmann, Eva, Jung, Manfred ORCID: 0000-0002-6361-7716, Buettner, Reinhard and Schuele, Roland (2015). The histone code reader SPIN1 controls RET signaling in liposarcoma. Oncotarget, 6 (7). S. 4773 - 4790. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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Abstract

The histone code reader Spindlin1 (SPIN1) has been implicated in tumorigenesis and tumor growth, but the underlying molecular mechanisms remain poorly understood. Here, we show that reducing SPIN1 levels strongly impairs proliferation and increases apoptosis of liposarcoma cells in vitro and in xenograft mouse models. Combining signaling pathway, genome-wide chromatin binding, and transcriptome analyses, we found that SPIN1 directly enhances expression of GDNF, an activator of the RET signaling pathway, in cooperation with the transcription factor MAZ. Accordingly, knockdown of SPIN1 or MAZ results in reduced levels of GDNF and activated RET explaining diminished liposarcoma cell proliferation and survival. In line with these observations, levels of SPIN1, GDNF, activated RET, and MAZ are increased in human liposarcoma compared to normal adipose tissue or lipoma. Importantly, a mutation of SPIN1 within the reader domain interfering with chromatin binding reduces liposarcoma cell proliferation and survival. Together, our data describe a molecular mechanism for SPIN1 function in liposarcoma and suggest that targeting SPIN1 chromatin association with small molecule inhibitors may represent a novel therapeutic strategy.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Franz, Henriette UNSPECIFIED orcid.org/0000-0001-9358-7442 UNSPECIFIED Greschik, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Willmann, Dominica UNSPECIFIED UNSPECIFIED UNSPECIFIED Ozretic, Luka UNSPECIFIED UNSPECIFIED UNSPECIFIED Jilg, Cordula Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Wardelmann, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Jung, Manfred UNSPECIFIED orcid.org/0000-0002-6361-7716 UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuele, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-405029
DOI:	10.18632/oncotarget.3000
Journal or Publication Title:	Oncotarget
Volume:	6
Number:	7
Page Range:	S. 4773 - 4790
Date:	2015
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ZINC-FINGER PROTEIN; MEDULLARY-THYROID CANCER; TUDOR-LIKE DOMAINS; MYXOID LIPOSARCOMAS; ANDROGEN-RECEPTOR; BREAST-CANCER; SPINDLIN1; MAZ; TRANSCRIPTION; METHYLATION Multiple languages Oncology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40502