TY - JOUR
T1 - The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis
AU - Wegwitz, Florian
AU - Prokakis, Evangelos
AU - Pejkovska, Anastasija
AU - Kosinsky, Robyn Laura
AU - Glatzel, Markus
AU - Pantel, Klaus
AU - Wikman, Harriet
AU - Johnsen, Steven A.
N1 - Funding Information:
We would like to thank S. Bolte, N. Molitor, and the staff of the European Neuroscience Institute Göttingen for assistance in the animal handling administration, F. Alves (Translational Molecular Imaging, Max Planck Institute for Experimental Medicine, Göttingen) for access to the IncuCyte® Live Cell Analysis System (Sartorius AG), S. Lutz (Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen) for providing the vinculin antibody, and M. Dobbelstein for reagents for measuring caspase 3/7 activity (Department of Molecular Oncology, Göttingen). Also, we want to thank our colleagues Ana Patricia Kutchat and Xin Wang for their productive input. This work was supported by funding from the Deutsche Krebshilfe to S. A.J. (1352320), and to H.W. and K.P. (Priority Program “Translational Oncology”; 70112507). Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/10/1
Y1 - 2020/10/1
N2 - The HER2-positive breast cancer subtype (HER2+-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2+-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment strategies. Epigenetic regulators are commonly misregulated in cancer and represent attractive molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by the heterodimeric ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2+-BC. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin-cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2+-BC, revealing the H2B monoubiquitination axis as a possible tumor context-dependent therapeutic target in breast cancer.
AB - The HER2-positive breast cancer subtype (HER2+-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2+-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment strategies. Epigenetic regulators are commonly misregulated in cancer and represent attractive molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by the heterodimeric ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2+-BC. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin-cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2+-BC, revealing the H2B monoubiquitination axis as a possible tumor context-dependent therapeutic target in breast cancer.
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U2 - 10.1038/s41419-020-03081-w
DO - 10.1038/s41419-020-03081-w
M3 - Article
C2 - 33070155
AN - SCOPUS:85092731197
SN - 2041-4889
VL - 11
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 10
M1 - 873
ER -