1] Gene Regulation, Stem Cells and Cancer, Centre de Regulació Genómica (CRG), Barcelona, Spain [2] Univeristat Pompeu Fabra (UPF), Barcelona, Spain.
Cardiovascular Research Center, CSIC-ICCC, CIBER-BBN, Barcelona, Spain.
Oncogene. 2014 Mar 20;33(12):1570-80. doi: 10.1038/onc.2013.95. Epub 2013 Apr 22.
Growth of breast cancers is often dependent on ovarian steroid hormones making the tumors responsive to antagonists of hormone receptors. However, eventually the tumors become hormone independent, raising the need to identify downstream targets for the inhibition of tumor growth. One possibility is to focus on the signaling mechanisms used by ovarian steroid hormones to induce breast cancer cell proliferation. Here we report that the mitogen- and stress-activated kinase 1 (MSK1) could be a potential druggable target. Using the breast cancer cell line T47D, we show that estrogens (E2) and progestins activate MSK1, which forms a complex with the corresponding hormone receptor. Inhibition of MSK1 activity with H89 or its depletion by MSK1 short hairpin RNAs (shRNAs) specifically abrogates cell proliferation in response to E2 or progestins without affecting serum-induced cell proliferation. MSK1 activity is required for the transition from the G1- to the S-phase of the cell cycle and inhibition of MSK1 compromises both estradiol- and progestin-dependent induction of cell cycle genes. ChIP-seq experiments identified binding of MSK1 to progesterone receptor-binding sites associated with hormone-responsive genes. MSK1 recruitment to epigenetically defined enhancer regions supports the need of MSK1 as a chromatin remodeler in hormone-dependent regulation of gene transcription. In agreement with this interpretation, expression of a histone H3 mutated at S10 eliminates the hormonal effect on cell proliferation and on induction of relevant target genes. Finally, we show that E2- or progestin-dependent growth of T47D cells xenografted in immunodefficient mice is inhibited by depletion of MSK1, indicating that our findings are not restricted to cultured cells, and that MSK1 plays an important role for hormone-dependent breast cancer growth in a more physiological context.
乳腺癌的生长通常依赖于卵巢类固醇激素，使肿瘤对激素受体拮抗剂有反应。然而，肿瘤最终会变得对激素不依赖，这就需要确定抑制肿瘤生长的下游靶点。一种可能性是关注卵巢类固醇激素用于诱导乳腺癌细胞增殖的信号转导机制。在这里，我们报告丝裂原和应激激活激酶 1（MSK1）可能是一个潜在的可药物治疗的靶点。使用乳腺癌细胞系 T47D，我们表明雌激素（E2）和孕激素激活 MSK1，MSK1 与相应的激素受体形成复合物。用 H89 抑制 MSK1 活性或用 MSK1 短发夹 RNA（shRNA）使其耗竭，特异性地阻断了对 E2 或孕激素的细胞增殖反应，而不影响血清诱导的细胞增殖。MSK1 活性是细胞周期从 G1 期到 S 期转变所必需的，抑制 MSK1 会损害雌二醇和孕激素依赖性细胞周期基因的诱导。ChIP-seq 实验鉴定了 MSK1 与孕激素受体结合位点的结合，这些结合位点与激素反应基因相关。MSK1 募集到表观遗传定义的增强子区域支持 MSK1 作为激素依赖性基因转录调控中的染色质重塑酶的需要。这一解释与以下发现一致，即 S10 位突变的组蛋白 H3 的表达消除了激素对细胞增殖和相关靶基因诱导的影响。最后，我们表明，在免疫缺陷小鼠中异种移植的 T47D 细胞的 E2 或孕激素依赖性生长被 MSK1 的耗竭所抑制，这表明我们的发现不仅限于培养细胞，而且 MSK1 在更生理的背景下对激素依赖性乳腺癌生长起着重要作用。
