Department of Hematology, Zhongshan People's Hospital, Zhongshan, 528403, Guangdong, China.
BMC Cancer. 2024 Sep 27;24(1):1189. doi: 10.1186/s12885-024-12886-3.
Histone acetylation plays a critical role in the progression of acute myeloid leukemia (AML). This study aimed to explore the prognostic significance and biological implications of histone acetylation-related genes in AML and to identify potential oncoproteins and therapeutic compounds.
Genes associated with AML and histone acetylation were identified using the TCGA-LAML and IMEx Interactome databases. A histone acetylation-related risk model was developed using the least absolute shrinkage and selection operator method. The prognostic value of the model was evaluated through Kaplan-Meier survival analysis, time-dependent receiver operating characteristic curve, univariate and multivariate Cox regression, and nomogram calibration. Key genes were identified using random forest, support vector machine, and multivariate Cox analysis. Molecular docking was employed to assess the binding affinity between ribosomal protein S6 kinase A1 (RPS6KA1) and potential compounds. Furthermore, the effects of RPS6KA1 and afzelin on the malignant behaviors and downstream pathways of AML cells were validated through in vitro experiments.
A risk model composed of 6 genes, including HDAC6, CREB3, KLF13, GOLGA2, RPS6KA1 and ZMIZ2, was established, demonstrating strong prognostic predictive capability. Among these, RPS6KA1 emerged as a key risk factor linked to histone acetylation status in AML. Elevated RPS6KA1 expression was observed in AML samples and was associated with poor prognosis. RPS6KA1 knockdown suppressed AML cell proliferation, migration, and invasion, induced G0/G1 phase arrest, and promoted apoptosis. Additionally, RPS6KA1 was identified as a potential target for afzelin, which exhibited anti-AML activity by inactivating RPS6KA1.
Histone acetylation status is closely associated with AML patient prognosis. RPS6KA1 acts as an oncoprotein in AML, facilitating disease progression. Afzelin may represent a novel therapeutic agent for AML by targeting RPS6KA1, which requires validation by clinical trials.
组蛋白乙酰化在急性髓系白血病（AML）的进展中起着关键作用。本研究旨在探讨 AML 中组蛋白乙酰化相关基因的预后意义和生物学意义，并确定潜在的癌蛋白和治疗化合物。
使用 TCGA-LAML 和 IMEx Interactome 数据库鉴定与 AML 和组蛋白乙酰化相关的基因。使用最小绝对收缩和选择算子（LASSO）方法构建组蛋白乙酰化相关风险模型。通过 Kaplan-Meier 生存分析、时间依赖性接受者操作特征曲线、单变量和多变量 Cox 回归以及列线图校准评估模型的预后价值。使用随机森林、支持向量机和多变量 Cox 分析鉴定关键基因。采用分子对接评估核糖体蛋白 S6 激酶 A1（RPS6KA1）与潜在化合物的结合亲和力。此外，通过体外实验验证了 RPS6KA1 和蛇葡萄素对 AML 细胞恶性行为和下游途径的影响。
构建了一个由 6 个基因组成的风险模型，包括 HDAC6、CREB3、KLF13、GOLGA2、RPS6KA1 和 ZMIZ2，该模型具有很强的预后预测能力。其中，RPS6KA1 是与 AML 中组蛋白乙酰化状态相关的关键风险因素。在 AML 样本中观察到 RPS6KA1 表达升高，与预后不良相关。RPS6KA1 敲低抑制 AML 细胞增殖、迁移和侵袭，诱导 G0/G1 期阻滞，并促进细胞凋亡。此外，RPS6KA1 被鉴定为蛇葡萄素的潜在靶标，蛇葡萄素通过使 RPS6KA1 失活来发挥抗 AML 活性。
组蛋白乙酰化状态与 AML 患者的预后密切相关。RPS6KA1 是 AML 中的癌蛋白，促进疾病进展。蛇葡萄素可能通过靶向 RPS6KA1 成为 AML 的一种新型治疗药物，这需要临床试验的验证。
