Characterization of a novel HDAC/RXR/HtrA1 signaling axis as a novel target to overcome cisplatin resistance in human non-small cell lung cancer
Characterization of a novel HDAC/RXR/HtrA1 signaling axis as a novel target to overcome cisplatin resistance in human non-small cell lung cancer
复制标题
新型 HDAC/RXR/HtrA1 信号轴作为克服人类非小细胞肺癌顺铂耐药性的新靶点的表征
DOI：
10.1186/s12943-020-01256-9
复制
发表时间：
2020-09-02
期刊：
影响因子：
37.3
通讯作者：
Wang, Lihui
中科院分区：
文献类型：
--
作者：
Wang, Wenjing;Zhao, Mengyue;Wang, Lihui
背景顺铂是治疗非小细胞肺癌（NSCLC）的一线药物，但大多数患者在治疗后会产生耐药。为了克服顺铂耐药性，重要的是要了解耐药性的机制。方法应用基因芯片技术筛选NSCLC细胞系顺铂耐药相关基因。随后，使用基因操作验证NSCLC中HDAC、RXR和HtrA 1基因之间的相关性。免疫组化法检测HDAC、RXR和HtrA 1在NSCLC组织中的表达。在体外和体内进行增殖，迁移和侵袭试验，以确定HDAC/RXR/HtrA 1信号轴在顺铂耐药中的作用，并进行荧光素酶报告基因分析和ChIP试验，以确定HDAC和RXR调节HtrA 1表达的机制。此外，在NSCLC顺铂耐药NSCLC中进行了体外和体内实验，以阐明靶向NSCLC顺铂耐药HDAC/RXR/HtrA 1信号通路的低分子量化合物DW 22的作用。结果HtrA 1是NSCLC细胞中顺铂耐药相关基因。HDAC和RXR对HtrA 1的调节显著降低了顺铂在对顺铂耐药的NSCLC细胞中的疗效。免疫组化结果显示，NSCLC组织中HDAC 1与HtrA 1呈负相关，RXR α与HtrA 1呈正相关。值得注意的是，HDAC 1和HtrA 1的表达可以被认为是NSCLC患者中铂类药物疗效和预后的生物标志物。在机制上，核受体RXR的异二聚体与酶HDAC组合调节NSCLC细胞中HtrA 1的转录。通过用化合物DW 22双重靶向HDAC和RXR来拯救HtrA 1表达，显著抑制对顺铂耐药的NSCLC细胞的增殖、迁移和侵袭，并诱导NSCLC细胞凋亡。结论HDAC和RXR协同调控NSCLC顺铂耐药相关基因HtrA 1的表达。靶向HDAC/RXR/HtrA 1信号轴可以拯救NSCLC中的HtrA 1表达并逆转顺铂耐药。
Background Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance. Methods A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway. Results HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXR alpha and HtrA1 in NSCLC patients' tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis. Conclusion Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.