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CCAAT/Enhancer binding protein β controls androgen-deprivation-induced senescence in prostate cancer cells

Oncogene volume 34, pages 5912–5922 (2015)Cite this article

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Abstract

The processes associated with transition to castration-resistant prostate cancer (PC) growth are not well understood. Cellular senescence is a stable cell cycle arrest that occurs in response to sublethal stress. It is often overcome in malignant transformation to confer a survival advantage. CCAAT/Enhancer Binding Protein (C/EBP) β function is frequently deregulated in human malignancies and interestingly, androgen-sensitive PC cells express primarily the liver-enriched inhibitory protein isoform. We found that C/EBPβ expression is negatively regulated by androgen receptor (AR) activity and that treatment of androgen-sensitive cell lines with anti-androgens increases C/EBPβ mRNA and protein levels. Accordingly, we also find that C/EBPβ levels are significantly elevated in primary PC samples from castration-resistant compared with therapy-naive patients. Chromatin immunoprecipitation demonstrated enhanced binding of the AR to the proximal promoter of the CEBPB gene in the presence of dihydroxytestosterone. Upon androgen deprivation, induction of C/EBPβ is facilitated by active transcription as evident by increased histone 3 acetylation at the C/EBPβ promoter. Also, the androgen agonist R1881 suppresses the activity of a CEBPB promoter reporter. Loss of C/EBPβ expression prevents growth arrest following androgen deprivation or anti-androgen challenge. Accordingly, suppression of C/EBPβ under low androgen conditions results in reduced expression of senescence-associated secretory genes, significantly decreased number of cells displaying heterochromatin foci and increased numbers of Ki67-positive cells. Ectopic expression of C/EBPβ caused pronounced morphological changes, reduced PC cell growth and increased the number of senescent LNCaP cells. Lastly, we found that senescence contributes to PC cell survival under androgen deprivation, and C/EBPβ-deficient cells were significantly more susceptible to killing by cytotoxic chemotherapy following androgen deprivation. Our data demonstrate that upregulation of C/EBPβ is critical for complete maintenance of androgen deprivation-induced senescence and that targeting C/EBPβ expression may synergize with anti-androgen or chemotherapy in eradicating PC.

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Acknowledgements

This research was supported by grants from the St Baldrick’s Foundation (to IP-P), the Mitchell Foundation (to IP-P), the Walsh Prostate Cancer Research Fund (to IP-P and ADF), the Samuel Waxman Cancer Research Foundation (to ADF), Department of Defense grant PC131609 (to DJB), National Institutes of Health T32 CA60441 (to TB), the Giant Food Children’s Cancer Research Fund and P30 CA006973.

Author Contributions

DJB designed and performed the research, analyzed data and wrote the manuscript; JZ and TB performed the research; SRD designed the research and analyzed data; ADF designed the research, analyzed data and wrote the manuscript; IP-P designed and performed the research, analyzed data and wrote the manuscript.

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  1. Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    D J Barakat, J Zhang, T Barberi, A D Friedman & I Paz-Priel

  2. Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    S R Denmeade

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  1. D J Barakat
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Correspondence to I Paz-Priel.

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Barakat, D., Zhang, J., Barberi, T. et al. CCAAT/Enhancer binding protein β controls androgen-deprivation-induced senescence in prostate cancer cells. Oncogene 34, 5912–5922 (2015). https://doi.org/10.1038/onc.2015.41

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