Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Taipei, 115, Taiwan.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Hematol Oncol. 2019 Jan 29;12(1):12. doi: 10.1186/s13045-019-0698-5.
Adenylate kinase 4 (AK4) has been identified as a biomarker of metastasis in lung cancer. However, the impacts of AK4 on metabolic genes and its translational value for drug repositioning remain unclear.
Ingenuity upstream analyses were used to identify potential transcription factors that regulate the AK4 metabolic gene signature. The expression of AK4 and its upstream regulators in lung cancer patients was examined via immunohistochemistry. Pharmacological and gene knockdown/overexpression approaches were used to investigate the interplay between AK4 and its upstream regulators during epithelial-to-mesenchymal transition (EMT). Drug candidates that reversed AK4-induced gene expression were identified by querying a connectivity map. Orthotopic xenograft mouse models were established to evaluate the therapeutic efficacy of drug candidates for metastatic lung cancer.
We found that HIF-1α is activated in the AK4 metabolic gene signature. IHC analysis confirmed this positive correlation, and the combination of both predicts worse survival in lung cancer patients. Overexpression of AK4 exaggerates HIF-1α protein expression by increasing intracellular ROS levels and subsequently induces EMT under hypoxia. Attenuation of ROS production with N-acetylcysteine abolishes AK4-induced invasion potential under hypoxia. Pharmacogenomics analysis of the AK4 gene signature revealed that withaferin-A could suppress the AK4-HIF-1α signaling axis and serve as a potent anti-metastatic agent in lung cancer.
Overexpression of AK4 promotes lung cancer metastasis by enhancing HIF-1α stability and EMT under hypoxia. Reversing the AK4 gene signature with withaferin-A may serve as a novel therapeutic strategy to treat metastatic lung cancer.
腺苷酸激酶 4（AK4）已被确定为肺癌转移的生物标志物。然而，AK4 对代谢基因的影响及其在药物再定位方面的翻译价值尚不清楚。
使用Ingenuity 上游分析来确定调节 AK4 代谢基因特征的潜在转录因子。通过免疫组织化学检查肺癌患者中 AK4 及其上游调节剂的表达。采用药理学和基因敲低/过表达方法研究上皮-间充质转化（EMT）过程中 AK4 与其上游调节剂之间的相互作用。通过查询连接组学来确定逆转 AK4 诱导的基因表达的候选药物。建立原位异种移植小鼠模型，以评估候选药物治疗转移性肺癌的疗效。
我们发现 HIF-1α 在 AK4 代谢基因特征中被激活。免疫组织化学分析证实了这种正相关，并且两者的组合预测肺癌患者的生存情况更差。AK4 的过表达通过增加细胞内 ROS 水平来夸大 HIF-1α 蛋白表达，进而在缺氧下诱导 EMT。用 N-乙酰半胱氨酸抑制 ROS 产生可消除 AK4 诱导的缺氧下的侵袭潜能。AK4 基因特征的药物基因组学分析表明，醉茄内酯 A 可以抑制 AK4-HIF-1α 信号轴，并作为一种有效的抗肺癌转移剂。
AK4 的过表达通过增强缺氧下的 HIF-1α 稳定性和 EMT 促进肺癌转移。用醉茄内酯 A 逆转 AK4 基因特征可能是治疗转移性肺癌的一种新的治疗策略。
