Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells.
Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells.
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DOI：
10.1016/j.jsbmb.2015.09.037
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Campbell MJ
中科院分区：
文献类型：
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作者：
Doig CL;Battaglia S;Khanim FL;Bunce CM;Campbell MJ
醛酮还原酶1C3（AKR1C3）与前列腺恶性肿瘤的发生密切相关。AKR1C3蛋白在前列腺癌组织中升高，它有助于雄激素的形成和雄激素受体（AR）的下游刺激。在急性髓性白血病中也报道了AKR1C3的表达升高，但靶核受体已被鉴定为过氧化物酶体增殖物激活受体（PPARs）亚家族的成员。因此，AKR1C3癌症生物学很可能是组织依赖性的，并且与类固醇生成和非类固醇生成核受体的配体的可用性相关。在目前的研究中，我们研究了AKR1C3调节胰高血糖素衍生的PPARg配体（主要是前列腺素J2（PGJ2））的可用性的潜力。使用具有稳定降低的AKR1C3水平的前列腺癌细胞系，我们检查了AKR1C3对由PPAR配体介导的增殖的影响。这些研究揭示AKR1C3的敲低对雄激素受体非依赖性前列腺癌细胞对PPAR配体的敏感性没有影响。然而，AKR1C3水平的降低伴随着一系列HDAC、转录辅助调节因子的mRNA表达显著降低，以及对临床批准的组蛋白脱乙酰酶抑制剂SAHA的敏感性增加。这些结果表明AKR1C3水平与前列腺癌细胞中的表观遗传状态之间存在迄今尚未确定的联系。这提出了靶向AKR1C3的新的合理性的有趣的可能性，AKRIC3选择性抑制剂与HDAC抑制的组合的利用作为雄激素剥夺疗法复发性前列腺癌中的新的表观遗传疗法的一部分。
The aldo-keto reductase 1C3 (AKR1C3) has been heavily implicated in the propagation of prostate malignancy. AKR1C3 protein is elevated within prostate cancer tissue, it contributes to the formation of androgens and downstream stimulation of the androgen receptor (AR). Elevated expression of AKR1C3 is also reported in acute myeloid leukemia but the target nuclear receptors have been identified as members of the peroxisome-proliferator activated receptor (PPARs) subfamily. Thus, AKR1C3 cancer biology is likely to be tissue dependent and hormonally linked to the availability of ligands for both the steroidogenic and non-steroidogenic nuclear receptors. In the current study we investigated the potential for AKR1C3 to regulate the availability of prostaglandin-derived ligands for PPARg mainly, prostaglandin J2 (PGJ2). Using prostate cancer cell lines with stably reduced AKR1C3 levels we examined the impact of AKR1C3 upon proliferation mediated by PPAR ligands. These studies revealed knockdown of AKR1C3 had no effect upon the sensitivity of androgen receptor independent prostate cancer cells towards PPAR ligands. However, the reduction of levels of AKR1C3 was accompanied by a significantly reduced mRNA expression of a range of HDACs, transcriptional co-regulators, and increased sensitivity towards SAHA, a clinically approved histone deacetylase inhibitor. These results suggest a hitherto unidentified link between AKR1C3 levels and the epigenetic status in prostate cancer cells. This raises an interesting possibility of a novel rational to target AKR1C3, the utilization of AKRIC3 selective inhibitors in combination with HDAC inhibition as part of novel epigenetic therapies in androgen deprivation therapy recurrent prostate cancer.