Research Papers:

The histone code reader SPIN1 controls RET signaling in liposarcoma

Henriette Franz _, Holger Greschik, Dominica Willmann, Luka Ozretić, Cordula Annette Jilg, Eva Wardelmann, Manfred Jung, Reinhard Buettner and Roland Schüle

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Oncotarget. 2015; 6:4773-4789. https://doi.org/10.18632/oncotarget.3000

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Henriette Franz1, Holger Greschik1, Dominica Willmann1, Luka Ozretić2, Cordula Annette Jilg1, Eva Wardelmann3, Manfred Jung4,6, Reinhard Buettner2, Roland Schüle1,5,6

1Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany

2Universitätsklinikum Köln, Institut für Pathologie, Köln, Germany

3Universitätsklinikum Münster, Gerhard-Domagk-Insitut für Pathologie, Münster, Germany

4Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany

5BIOSS Centre of Biological Signaling Studies, Albert-Ludwigs-University, Freiburg, Germany

6Deutsches Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Germany

Correspondence to:

Roland Schüle, e-mail: [email protected]

Keywords: SPIN1, histone code reader, GDNF, RET signaling, MAZ

Received: October 30, 2014     Accepted: December 21, 2014     Published: February 25, 2015


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.

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