The histone code reader SPIN1 controls RET signaling in liposarcoma.
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.
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
Henriette
H
Franz
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
Holger
H
Greschik
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
Dominica
D
Willmann
Universitätsklinikum Köln, Institut für Pathologie, Köln, Germany.
Luka
L
Ozretić
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
Cordula Annette
CA
Jilg
Universitätsklinikum Münster, Gerhard-Domagk-Insitut für Pathologie, Münster, Germany.
Eva
E
Wardelmann
Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.|Deutsches Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Germany.
Manfred
M
Jung
Universitätsklinikum Köln, Institut für Pathologie, Köln, Germany.
Reinhard
R
Buettner
Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.|BIOSS Centre of Biological Signaling Studies, Albert-Ludwigs-University, Freiburg, Germany.|Deutsches Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Germany.
Roland
R
Schüle
D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D042421:Histone Code; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008067:Lipoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008080:Liposarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C104434:spindlin; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
GDNF; MAZ; RET signaling; SPIN1; histone code reader