Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored. We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance. Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2. Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.

中文翻译：

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EHMT2/NFYA-ALDH2信号轴调节RAF通路调节肺癌紫杉醇耐药

肺癌是一种在世界范围内发病率和死亡率都很高的恶性肿瘤。紫杉醇（PTX）是非小细胞肺癌（NSCLC）的主要治疗药物，对PTX的耐药严重影响患者的生存。然而，潜在的机制和潜在的逆转策略需要进一步探索。我们使用基因微阵列分析将 ALDH2 鉴定为 PTX 抗性相关基因。随后，对细胞系、患者样本和异种移植模型进行了一系列功能分析，探讨了ALDH2在NSCLC PTX耐药中的功能作用、临床意义和异常调控机制。此外，靶向 ALDH2 和表观遗传酶的药物被用于研究对抗 PTX 耐药性的多种逆转策略。使用 NSCLC 细胞的体外和体内分析以及 NSCLC 患者的临床病理学分析，ALDH2 表达的上调与对 PTX 的抗性高度相关。过表达 ALDH2 的 NSCLC 细胞表现出显着降低的 PTX 敏感性和增加的体外恶性肿瘤生物学特征和体内肿瘤生长和转移。EHMT2（常染色组蛋白赖氨酸甲基转移酶2）抑制和NFYA（核转录因子Y亚基α）过表达对ALDH2的调节有协同作用。从机制上讲，ALDH2 过表达激活了 RAS/RAF 致癌途径。当 ALDH2 被包括 ALDH2 抑制剂大豆苷 (DZN)/双硫仑 (DSF) 和 JIB04 在内的药物抑制时，NSCLC/PTX 细胞在体内和体外重新获得对 PTX 的敏感性，这逆转了 EHMT2 的作用。我们的研究结果表明，ALDH2 状态可以帮助预测患者对 PTX 治疗的反应，而 ALDH2 抑制可能是临床上克服 PTX 耐药性的有希望的策略。