Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated to Dalian Medical University, Dalian, Liaoning 116033, P.R. China.
Int J Mol Med. 2018 Jun;41(6):3366-3378. doi: 10.3892/ijmm.2018.3519. Epub 2018 Feb 28.
Overexpression of c-Myc is involved in the tumorigenesis of B-lineage acute lymphoblastic leukemia (B‑ALL), but the mechanism is not well understood. In the present study, a c‑Myc‑knockdown model (Raji‑KD) was established using Raji cells, and it was indicated that c‑Myc regulates the expression of genes associated with cell cycle progression in G2/M‑phase, cyclin D kinase (CDK)1 and cyclin B1, by modulating 60 kDa Tat‑interactive protein (TIP60)/males absent on the first (MOF)‑mediated histone H4 acetylation (AcH4), which was then completely restored by re‑introduction of the c‑Myc gene into the Raji‑KD cells. The expression of CDK1 and cyclin B1 was markedly suppressed in Raji‑KD cells, resulting in G2/M arrest. In comparison to Raji cells, the proliferation of Raji‑KD cells was significantly reduced, and it was recovered via re‑introduction of the c‑Myc gene. In the tumorigenesis assays, the loss of c‑Myc expression significantly suppressed Raji cell‑derived lymphoblastic tumor formation. Although c‑Myc also promotes Raji cell apoptosis via the caspase‑3‑associated pathway, CDK1/cyclin B1‑dependent‑G2/M cell cycle progression remains the major driving force of c‑Myc‑controlled tumorigenesis. The present results suggested that c‑Myc regulates cyclin B1‑ and CDK1‑dependent G2/M cell cycle progression by TIP60/MOF-mediated AcH4 in Raji cells.
c-Myc 的过表达与 B 细胞急性淋巴细胞白血病（B-ALL）的肿瘤发生有关，但具体机制尚不清楚。在本研究中，使用 Raji 细胞建立了 c-Myc 敲低模型（Raji-KD），结果表明 c-Myc 通过调节 60kDa Tat 相互作用蛋白（TIP60）/雄性缺失于第一（MOF）介导的组蛋白 H4 乙酰化（AcH4）来调节与 G2/M 期细胞周期进展相关的基因的表达，随后通过重新引入 c-Myc 基因完全恢复 Raji-KD 细胞中的 TIP60/ MOF 介导的 AcH4。CDK1 和 cyclin B1 的表达在 Raji-KD 细胞中明显受到抑制，导致 G2/M 期阻滞。与 Raji 细胞相比，Raji-KD 细胞的增殖明显减少，通过重新引入 c-Myc 基因得到恢复。在肿瘤发生实验中，c-Myc 表达的丧失显著抑制了 Raji 细胞衍生的淋巴母细胞瘤的形成。尽管 c-Myc 还通过 caspase-3 相关途径促进 Raji 细胞凋亡，但 CDK1/cyclin B1 依赖性 G2/M 细胞周期进程仍然是 c-Myc 控制肿瘤发生的主要驱动力。本研究结果表明，c-Myc 通过 TIP60/ MOF 介导的 AcH4 调节 Raji 细胞中 cyclin B1 和 CDK1 依赖性 G2/M 细胞周期进程。
