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SUPT6H controls estrogen receptor activity and cellular differentiation by multiple epigenomic mechanisms

Oncogene volume 34, pages 465–473 (2015)Cite this article

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Abstract

The estrogen receptor alpha (ERα) is the central transcriptional regulator of ductal mammary epithelial lineage specification and is an important prognostic marker in human breast cancer. Although antiestrogen therapies are initially highly effective at treating ERα-positive tumors, a large number of tumors progress to a refractory, more poorly differentiated phenotype accompanied by reduced survival. A better understanding of the molecular mechanisms involved in the progression from estrogen-dependent to hormone-resistant breast cancer may uncover new targets for treatment and the discovery of new predictive markers. Recent studies have uncovered an important role for transcriptional elongation and chromatin modifications in controlling ERα activity and estrogen responsiveness. The human Suppressor of Ty Homologue-6 (SUPT6H) is a histone chaperone that links transcriptional elongation to changes in chromatin structure. We show that SUPT6H is required for estrogen-regulated transcription and the maintenance of chromatin structure in breast cancer cells, possibly in part through interaction with RNF40 and regulation of histone H2B monoubiquitination (H2Bub1). Moreover, we demonstrate that SUPT6H protein levels decrease with malignancy in breast cancer. Consistently, SUPT6H, similar to H2Bub1, is required for cellular differentiation and suppression of the repressive histone mark H3K27me3 on lineage-specific genes. Together, these data identify SUPT6H as a new epigenetic regulator of ERα activity and cellular differentiation.

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Acknowledgements

We thank L Schreiber, J Schiller and CR Schlegel for initial efforts in establishing SUPT6H knockdown. UB was supported by doctoral fellowships from the Erasmus Mundus External Cooperation Window EURINDIA and the Göttingen Graduate School for Neurosciences, Biophysics and Molecular Biosciences. This work was supported by grants from the Deutsche Krebshilfe (109088) and the Deutsche Forschungsgemeinschaft (JO 815/3) to SAJ.

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Authors and Affiliations

  1. Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany

    U Bedi & S A Johnsen

  2. Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany

    U Bedi, M Hennion, Y Begus-Nahrmann & S A Johnsen

  3. Institute of Pathology Nordhessen, Kassel, Germany

    A H Scheel & J Rüschoff

  4. Department of Pathology, Center for Pathology and Forensic Medicine, University Medical Center Göttingen, Göttingen, Germany

    A H Scheel

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  1. U Bedi
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Correspondence to S A Johnsen.

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Bedi, U., Scheel, A., Hennion, M. et al. SUPT6H controls estrogen receptor activity and cellular differentiation by multiple epigenomic mechanisms. Oncogene 34, 465–473 (2015). https://doi.org/10.1038/onc.2013.558

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