Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, via Adamello 16, 20139 Milan, Italy
Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, via Adamello 16, 20139 Milan, Italy.
J Mol Cell Biol. 2015 Apr;7(2):132-42. doi: 10.1093/jmcb/mjv021. Epub 2015 Mar 23.
Histone deacetylase 1 (HDAC1) is an important epigenetic controller involved in transcriptional regulation through modification of chromatin structure. Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer. Downregulation of estrogen receptor α (ERα) expression is one of the mechanisms behind the acquisition of endocrine resistance. Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy. Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer, reversing also acquired hormone resistance. Here we show how mitogens, activating the PI3K/mTOR pathway, trigger the phosphorylation of HDAC1 in breast cancer cells, which is completely dependent on the activity of the p70 S6 kinase (S6K1). Our findings show that S6K1, overexpressed in many breast cancers, controls HDAC1-dependent transcriptional regulation of ERα levels upon mitogenic stimuli, controlling HDAC1 recruitment to the ERα promoter. Furthermore, cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation. This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.
组蛋白去乙酰化酶 1（HDAC1）是一种重要的表观遗传调控因子，通过修饰染色质结构参与转录调控。遗传和表观遗传变化以及信号转导途径的失调与乳腺癌的发生有关。雌激素受体α（ERα）表达的下调是获得内分泌耐药的机制之一。乳腺癌细胞中持续和增加的激素和生长因子受体信号转导导致对内分泌治疗的耐药。HDAC 和 PI3K/mTOR 信号通路都成为乳腺癌有前途的治疗靶点，也可以逆转获得的激素耐药性。在这里，我们展示了有丝分裂原如何激活 PI3K/mTOR 途径，触发乳腺癌细胞中 HDAC1 的磷酸化，这完全依赖于 p70 S6 激酶（S6K1）的活性。我们的研究结果表明，在许多乳腺癌中过表达的 S6K1 控制有丝分裂原刺激下 ERα 水平的 HDAC1 依赖性转录调节，控制 HDAC1 向 ERα 启动子的募集。此外，用 mTOR 和 HDAC 抑制剂联合处理细胞可在抑制乳腺癌增殖方面产生相加作用。这证实了 HDAC1 和 PI3K 途径之间的新的串扰，对这种恶性疾病的治疗具有临床意义。
