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Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1

Oncogene volume 36, pages 1525–1536 (2017)Cite this article

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Abstract

Chronic behavioral stress and beta-adrenergic signaling have been shown to promote cancer progression, whose underlying mechanisms are largely unclear, especially the involvement of epigenetic regulation. Histone deacetylase-2 (HDAC2), an epigenetic regulator, is critical for stress-induced cardiac hypertrophy. It is unknown whether it is necessary for beta-adrenergic signaling-promoted cancer progression. Using xenograft models, we showed that chronic behavioral stress and beta-adrenergic signaling promote angiogenesis and prostate cancer progression. HDAC2 was induced by beta-adrenergic signaling in vitro and in mouse xenografts. We next uncovered that HDAC2 is a direct target of cAMP response element-binding protein (CREB) that is activated by beta-adrenergic signaling. Notably, HDAC2 is necessary for beta-adrenergic signaling to induce angiogenesis. We further demonstrated that, upon CREB activation, HDAC2 represses thrombospondin-1 (TSP1), a potent angiogenesis inhibitor, through epigenetic regulation. Together, these data establish a novel pathway that HDAC2 and TSP1 act downstream of CREB activation in beta-adrenergic signaling to promote cancer progression.

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Acknowledgements

We are grateful to Dr Rebecca Berdeaux for providing us the CREB cDNA constructs. We are thankful to Drs Isaiah Fidler and Vihang Narkar for providing us PC3 and SVEC4-10 cells, respectively. We also would like to thank Dr Kendra Carmon for critical reading of this paper. This work was supported by a Rising STARS Award from University of Texas System (W Li).

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Authors and Affiliations

  1. Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

    M Hulsurkar, Z Li, Y Zhang, X Li, D Zheng & W Li

  2. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    M Hulsurkar & W Li

  3. Breast and Thyroid Surgery Center, The Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Z Li

  4. The Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Y Zhang

  5. The Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, Liaocheng, China

    X Li

  6. Department of Medical Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    D Zheng

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Correspondence to W Li.

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Hulsurkar, M., Li, Z., Zhang, Y. et al. Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1. Oncogene 36, 1525–1536 (2017). https://doi.org/10.1038/onc.2016.319

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