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.
Keywords:
GDNF; MAZ; RET signaling; SPIN1; histone code reader.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipose Tissue / metabolism*
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Adipose Tissue / pathology
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Animals
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Apoptosis
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Blotting, Western
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / immunology
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Cell Cycle Proteins / metabolism*
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Cell Proliferation
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Chromatin Immunoprecipitation
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Fluorescent Antibody Technique
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Histone Code
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Lipoma / genetics
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Lipoma / metabolism*
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Lipoma / pathology
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Liposarcoma / genetics
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Liposarcoma / metabolism*
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Liposarcoma / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / immunology
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Microtubule-Associated Proteins / metabolism*
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / genetics
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Phosphoproteins / immunology
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Phosphoproteins / metabolism*
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Proto-Oncogene Proteins c-ret / genetics
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Proto-Oncogene Proteins c-ret / metabolism*
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Rabbits
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Analysis, RNA
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Signal Transduction*
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Cell Cycle Proteins
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Microtubule-Associated Proteins
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Phosphoproteins
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RNA, Messenger
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RNA, Small Interfering
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spindlin
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Proto-Oncogene Proteins c-ret
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RET protein, human