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  • Original Article
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let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery

Oncogene volume 36, pages 5819–5828 (2017)Cite this article

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Abstract

Monoubiquitylation of histone H2B (H2Bub1) is catalyzed mainly by the RNF20/RNF40 complex and erased by multiple deubiquitylating enzymes (DUBs). H2Bub1 influences many aspects of chromatin function, including transcription regulation and DNA repair. Cancer cells often display reduced levels of H2Bub1, and this reduction may contribute to cancer progression. The let-7 family of microRNAs (miRNAs) comprises multiple members with reported tumor-suppressive features, whose expression is frequently downregulated in cancer. We now report that let-7b and let-7c can positively regulate cellular H2Bub1 levels. Overexpression of let-7b and let-7c in a variety of non-transformed and cancer-derived cell lines results in H2Bub1 elevation. The positive effect of let-7b and let-7c on H2Bub1 levels is achieved through targeting of multiple mRNAs, coding for distinct components of the H2B deubiquitylation machinery. Specifically, let-7b and let-7c bind directly and inhibit the mRNAs encoding the DUBs USP42 and USP44, and also the mRNA encoding the adapter protein ATXN7L3, which is part of the DUB module of the SAGA complex. RNF20 knockdown (KD) strongly reduces H2Bub1 levels and increases the migration of non-transformed mammary epithelial cells and breast cancer-derived cells. Remarkably, overexpression of let-7b, which partly counteracts the effect of RNF20 KD on H2Bub1 levels, also reverses the pro-migratory effect of RNF20 KD. Likewise, ATXN7L3 KD also increases H2Bub1 levels and reduces cell migration, and this anti-migratory effect is abolished by simultaneous KD of RNF20. Together, our findings uncover a novel function of let-7 miRNAs as regulators of H2B ubiquitylation, suggesting an additional mechanism whereby these miRNAs can exert their tumor-suppressive effects.

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Acknowledgements

We thank Ofra Golani from the Bioinformatics Unit of the Weizmann Institute for expert help with image analysis; Yonit Hoffman and Gali Brand for help with data analysis; and Sharath Chandra Arandkar and Ohad Tarcic for valuable discussions. This study was supported in part by the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, grant 293438 (RUBICAN) from the European Research Council, a Center of Excellence grant from the Israel Science Foundation, the Robert Bosch Foundation (project 11.5.8000.0094) and the Moross Integrated Cancer Center. MO is incumbent of the Andre Lwoff chair in molecular biology.

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  1. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    A Spolverini, G Fuchs, D R Bublik & M Oren

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Spolverini, A., Fuchs, G., Bublik, D. et al. let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery. Oncogene 36, 5819–5828 (2017). https://doi.org/10.1038/onc.2017.187

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  • DOI: https://doi.org/10.1038/onc.2017.187

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