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BCOR-coupled H2A monoubiquitination represses a subset of androgen receptor target genes regulating prostate cancer proliferation

Oncogene volumeĀ 39,Ā pages 2391ā€“2407 (2020)Cite this article

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Abstract

We have identified BCL6 corepressor (BCOR) as a hormone-dependent interaction partner of androgen receptor (AR), a key transcription factor in the development of normal and cancerous prostate. BCOR is often mutated in cancers and hematological diseases and as a component of a non-canonical polycomb repressive complex 1 (ncPRC1.1) required for arranging many facets of cellular differentiation. However, its role in androgen signaling or prostate cancer cells remains unknown. Here, our genome-wide analyses reveal that BCOR is recruited in an androgen-dependent fashion to majority of AR-binding chromatin sites in castration-resistant prostate cancer (CRPC) cells. Interestingly, depletion of BCOR has a significant effect on the expression of androgen-repressed genes linked to regulation of cell proliferation, differentiation and development. At many of these genes, such as HOX genes, the depletion leads to a decrease in H2A K119 monoubiquitination and an increase in mRNA expression. Consistently, BCOR depletion impairs the proliferation and viability of CRPC cells, inducing their apoptosis. Collectively, our data indicate a key role for the BCOR-ncPRC1.1 complex in the corepression of an important subset of AR target genes and the regulation of prostate cancer cell proliferation.

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Fig. 1: BCOR is recruited to AR-binding sites on chromatin in prostate cancer cells.
Fig. 2: Monoubiquitination of H2A is androgen-regulated at multiple genes in prostate cancer cells.
Fig. 3: Depletion of BCOR influences AR target gene expression in prostate cancer cells.
Fig. 4: Depletion of BCOR leads to a decrease in H2A monoubiquitination, especially at androgen-repressed genes in prostate cancer cells.
Fig. 5: BCOR regulates H2A monoubiquitination and expression of HOX C cluster genes in prostate cancer cells.
Fig. 6: Depletion of BCOR attenuates the proliferation of prostate cancer cells and induces their apoptosis.

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Data availability

ChIP-seq and RNA-seq data have been deposited to the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE122572).

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Acknowledgements

We thank Merja RƤsƤnen and Eija Korhonen for assistance in cell culturing and plasmid and buffer preparing. The EMBL GeneCore is greatly acknowledged for deep sequencing, and the UEF Bioinformatics Center for providing computational infrastructure. The UEF Cell and Tissue Imaging Unit is greatly thanked for providing services and equipment for cell proliferation and apoptosis assays.

Funding

This work was supported by the Academy of Finland, the Cancer Foundation Finland, the Sigrid JusƩlius Foundation, the UEF Doctoral Programme in Molecular Medicine, the Jalmari and Rauha Ahokas Foundation, the Instrumentarium Foundation, the Orion Research Foundation, the Ida Montini Foundation and the Kuopio University Foundation.

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  1. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

    Joanna K. LempiƤinen,Ā A. B. M. Kaiser Manjur,Ā Marjo Malinen,Ā Kirsi Ketola,Ā Einari A. NiskanenĀ &Ā Jorma J. Palvimo

  2. Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland

    Marjo Malinen

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LempiƤinen, J.K., Manjur, A.B.M.K., Malinen, M. et al. BCOR-coupled H2A monoubiquitination represses a subset of androgen receptor target genes regulating prostate cancer proliferation. Oncogene 39, 2391ā€“2407 (2020). https://doi.org/10.1038/s41388-020-1153-3

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  • DOI: https://doi.org/10.1038/s41388-020-1153-3

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