有丝分裂期染色质的表观遗传调控与在随后细胞周期中基因重新表达密切相关。之前研究表明，有丝分裂调控紊乱与肿瘤发生发展密切相关；然而关于‘有丝分裂期表观遗传调控-基因重新表达’的调控在肿瘤中的作用机理尚不明确。我们前期研究发现有丝分裂阻滞导致p38对Bub3的磷酸化，促进Bub3与DNA甲基转移酶相关蛋白1(DMAP1)结合，以及胰腺癌细胞凋亡；而此效应被肿瘤细胞中高活性 c-Src所抑制；生化实验表明c-Src能够磷酸化DMAP1。提示c-Src异常活化会增强肿瘤细胞对于有丝分裂阻滞的抵抗能力。本项目拟研究：有丝分裂Bub3/DMAP1信号调控有丝分裂后基因重新表达的分子机制； c-Src抑制p38-Bub3-DMAP1信号通路在肿瘤抵抗有丝分裂阻滞中的作用； Bub3/DMAP1磷酸化与病人预后的相关性。本项目旨在阐明有丝分裂表观调节基因转录的分子机制以及其在肿瘤中的作用。

Epigenetic regulation of chromatin at mitosis is tightly linked to the proper transcriptional reactivation in the subsequent cell cycle. Previous studies indicated mitosis dysregulation is involved in tumorigenesis. However, how ‘mitosis epigenetic modification-gene reactivation’ plays a role in tumorigenesis is rarely investigated. In our preliminary study, we found mitotic arrest induced pancreatic cancer cell (PDAC) apoptosis and p38-dependent phosphorylation of Bub3, which promoted the interaction between Bub3 and DNA methytransferase 1 (DNMT1) associated protein, DMAP1; while these effects were blocked by the hyperactivation of c-Src in tumor cells. Biochemical analysis revealed c-Src phosphorylated DMAP1. These data suggested hyperactivated c-Src renders pancreatic cancer cell to resist mitosis arrest. In this project, we aim to further explore the molecular basis of mitosis Bub3/DMAP1 axis in gene reactivation, the cellular function of suppression p38-Bub3-DMAP1 signals by c-Src, and the prognosis of Bub3/DMAP1 phosphorylation in PDAC. This project will demonstrate the molecular underpinnings of mitosis epigenetic modification in gene transcription as well as its critical role in PDAC.