Hulsurkar M, Li Z, Zhang Y, Li X, Zheng D, Li W
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
Oncogene. 2017 Mar;36(11):1525-1536. doi: 10.1038/onc.2016.319. Epub 2016 Sep 19.
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.
慢性行为应激和β-肾上腺素能信号已被证明可促进癌症进展，但其潜在机制在很大程度上尚不清楚，尤其是表观遗传调控的参与情况。组蛋白去乙酰化酶2（HDAC2）作为一种表观遗传调节因子，对应激诱导的心脏肥大至关重要。目前尚不清楚它对于β-肾上腺素能信号促进癌症进展是否必要。利用异种移植模型，我们发现慢性行为应激和β-肾上腺素能信号可促进血管生成和前列腺癌进展。HDAC2在体外和小鼠异种移植模型中均由β-肾上腺素能信号诱导产生。接下来我们发现，HDAC2是由β-肾上腺素能信号激活的环磷酸腺苷反应元件结合蛋白（CREB）的直接靶点。值得注意的是，HDAC2是β-肾上腺素能信号诱导血管生成所必需的。我们进一步证明，在CREB激活后，HDAC2通过表观遗传调控抑制强效血管生成抑制剂血小板反应蛋白1（TSP1）。这些数据共同建立了一条新的信号通路，即HDAC2和TSP1在β-肾上腺素能信号传导中CREB激活的下游发挥作用，以促进癌症进展。
