The EMT transcription factor ZEB1 blocks osteoblastic differentiation in bone development and osteosarcoma

Osteosarcoma is an often‐fatal mesenchyme‐derived malignancy in children and young adults. Overexpression of EMT‐transcription factors (EMT‐TFs) has been associated with poor clinical outcome. Here, we demonstrated that the EMT‐TF ZEB1 is able to block osteoblastic differentiation in normal bone dev...

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Bibliographic Details
Published in:The Journal of pathology 2021-06, Vol.254 (2), p.199-211
Main Authors: Ruh, Manuel, Stemmler, Marc P, Frisch, Isabell, Fuchs, Kathrin, Roey, Ruthger, Kleemann, Julia, Roas, Maike, Schuhwerk, Harald, Eccles, Rebecca L, Agaimy, Abbas, Baumhoer, Daniel, Berx, Geert, Müller, Fabian, Brabletz, Thomas, Brabletz, Simone
Format: Article
Language:English
Subjects:
Animals
Bone cancer
Bone Development
Bone Neoplasms - drug therapy
Bone Neoplasms - pathology
Cell Differentiation
Cell Line
Cell Proliferation
EMT
Epigenetics
Epigenomics
Gene Expression
Gene Expression Regulation, Neoplastic
Humans
Malignancy
Mesenchymal Stem Cells - pathology
Mesenchyme
Metastases
metastatic colonization
Mice
MicroRNAs - genetics
miRNA
Osteoblastogenesis
Osteoblasts
Osteoblasts - pathology
Osteosarcoma
Osteosarcoma - drug therapy
Osteosarcoma - pathology
Osteosarcoma cells
Sarcoma
therapy
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
Young adults
ZEB1
Zinc Finger E-box-Binding Homeobox 1 - genetics
Zinc Finger E-box-Binding Homeobox 1 - metabolism
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Summary:Osteosarcoma is an often‐fatal mesenchyme‐derived malignancy in children and young adults. Overexpression of EMT‐transcription factors (EMT‐TFs) has been associated with poor clinical outcome. Here, we demonstrated that the EMT‐TF ZEB1 is able to block osteoblastic differentiation in normal bone development as well as in osteosarcoma cells. Consequently, overexpression of ZEB1 in osteosarcoma characterizes poorly differentiated, highly metastatic subgroups and its depletion induces differentiation of osteosarcoma cells. Overexpression of ZEB1 in osteosarcoma is frequently associated with silencing of the imprinted DLK‐DIO3 locus, which encodes for microRNAs targeting ZEB1. Epigenetic reactivation of this locus in osteosarcoma cells reduces ZEB1 expression, induces differentiation, and sensitizes to standard treatment, thus indicating therapeutic options for ZEB1‐driven osteosarcomas. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.5659