KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer
KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer
复制标题
KLF14 通过调节去势抵抗性前列腺癌中的 HO-1 信号传导来增强氧化适应。
DOI：
10.1530/erc-18-0383
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Li, Wei
中科院分区：
文献类型：
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作者：
Luo, Xiao-hui;Liu, Jian-zhou;Li, Wei
深入了解关键因素在雄激素耗竭条件下刺激细胞生长的机制是开发对去势抵抗性前列腺癌（CRPC）患者具有临床显著活性的有效治疗方法的前提。在此，我们报告，Krüppel样因子14（KLF 14），在调节脂质代谢的主转录因子的表达，显着诱导去势不敏感的PCa细胞和肿瘤组织从小鼠CRPC异种移植模型。氧化应激刺激前列腺癌细胞上游KLF 14表达上调，依赖于多种途径，包括PI 3 K/AKT、p42/p44 MAPK、AMPK和PKC途径。通过异位过表达和基因失活，我们进一步表明，KLF 14促进细胞生长，通过积极调节雄激素耗竭条件下的抗氧化反应。从机制上讲，KLF 14与p300和CBP偶联以增强HMOX 1的转录激活，HMOX 1是编码抗氧化酶血红素加氧酶-1（HO-1）的基因，是细胞适应应激的最重要机制之一。瞬时敲低HMOX 1足以克服KLF 14过表达增强的前列腺癌细胞在雄激素耗竭条件下的生长。从药理学的角度来看，体内给予ZnPPIX（HO-1的特异性抑制剂）可有效减弱小鼠异种移植模型中去势抵抗的进展，而不改变KLF 14水平。总之，这些结果提供了对KLF 14依赖性调节抗氧化反应和随后的去势抵抗发病机制的全面了解，并表明应进一步探索针对KLF 14/HO-1适应性机制的干预措施用于CRPC治疗。
Insights into the mechanisms by which key factors stimulate cell growth under androgen-depleted conditions is a premise to the development of effective treatments with clinically significant activity in patients with castration-resistant prostate cancer (CRPC). Herein, we report that, the expression of Krüppel-like factor 14 (KLF14), a master transcription factor in the regulation of lipid metabolism, was significantly induced in castration-insensitive PCa cells and tumor tissues from a mouse xenograft model of CRPC. KLF14 upregulation in PCa cells, which was stimulated upstream by oxidative stress, was dependent on multiple pathways including PI3K/AKT, p42/p44 MAPK, AMPK and PKC pathways. By means of ectopic overexpression and genetic inactivation, we further show that KLF14 promoted cell growth via positive regulation of the antioxidant response under androgen-depleted conditions. Mechanistically, KLF14 coupled to p300 and CBP to enhance the transcriptional activation of HMOX1, the gene encoding the antioxidative enzyme heme oxygenase-1 (HO-1) that is one of the most important mechanisms of cell adaptation to stress. Transient knockdown of HMOX1 is sufficient to overcome KLF14 overexpression-potentiated PCa cell growth under androgen-depleted conditions. From a pharmacological standpoint, in vivo administration of ZnPPIX (a specific inhibitor of HO-1) effectively attenuates castration-resistant progression in the mouse xenograft model, without changing KLF14 level. Together, these results provide comprehensive insight into the KLF14-dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for CRPC treatment.