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Updated: Apr 16, 2026
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Published on: February 1, 2020
The histone code reader SPIN1 controls RET signaling in liposarcoma
Henriette Franz1, Holger Greschik1, Dominica Willmann1
1Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
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.
Insights
Spindlin1 (SPIN1) protein drives liposarcoma growth by boosting GDNF and RET signaling. Inhibiting SPIN1’s chromatin binding offers a potential new therapy for liposarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Spindlin1 (SPIN1), a histone code reader, is linked to cancer but its precise role in liposarcoma is unclear.
- Understanding SPIN1's molecular mechanisms is crucial for developing targeted liposarcoma therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms by which SPIN1 influences liposarcoma cell proliferation and survival.
- To investigate the potential of targeting SPIN1 as a therapeutic strategy for liposarcoma.
Main Methods:
- In vitro and xenograft mouse models of liposarcoma.
- Signaling pathway analysis, genome-wide chromatin immunoprecipitation sequencing (ChIP-seq), and transcriptome analysis (RNA-seq).
- Analysis of SPIN1, MAZ, GDNF, and RET pathway activation in human liposarcoma tissues.
Main Results:
- Reduced SPIN1 levels impaired liposarcoma cell proliferation and increased apoptosis.
- SPIN1, in conjunction with MAZ, directly enhances Glial cell line-Derived Neurotrophic Factor (GDNF) expression, activating the RET signaling pathway.
- Knockdown of SPIN1 or MAZ decreased GDNF and activated RET, leading to reduced proliferation and survival.
- SPIN1, GDNF, activated RET, and MAZ are upregulated in human liposarcoma.
- A SPIN1 mutation disrupting chromatin binding reduced liposarcoma cell proliferation and survival.
Conclusions:
- SPIN1 promotes liposarcoma progression by enhancing the SPIN1-MAZ-GDNF-RET signaling axis.
- SPIN1's chromatin association is essential for its oncogenic function in liposarcoma.
- Targeting SPIN1's interaction with chromatin may offer a novel therapeutic avenue for liposarcoma.
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