The histone code reader SPIN1 controls RET signaling in liposarcoma

Oncotarget
Henriette FranzRoland Schüle

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.

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Datasets Mentioned

BETA
GSE57502

Methods Mentioned

BETA
dissection
transfection
xenograft
antibody array
immunoprecipitation
ChIP-seq
RNA-seq
PCR
coimmunoprecipitation
ChIP

Software Mentioned

Pathscan
IGV genome browser
ImageJ
DESeq
bowtie
MACS
WebGestalt
WebGestalt KEGG
HOMER
TopHat

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