C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer
C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer
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C-Src 通过抑制胰腺癌中 DMAP1/Bub3 复合物的形成赋予对有丝分裂应激的抵抗力
DOI：
10.1186/s12943-018-0919-5
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发表时间：
2018-12-15
期刊：
影响因子：
37.3
通讯作者：
Jiang, Yuhui
中科院分区：
文献类型：
--
作者：
Li, Jingjie;Hu, Bin;Jiang, Yuhui
背景有丝分裂时染色质的修饰与随后的细胞周期中转录的重新激活密切相关。我们推测，这一过程被癌基因信号解除调控，这将有助于胰腺癌的有丝分裂应激抵抗。在这里，我们发现DMAP1/Bub3复合体介导了有丝分裂应激诱导的细胞凋亡，而这一作用在胰腺癌细胞中被c-Src所抵消。我们的研究旨在揭示正常细胞和胰腺癌细胞对有丝分裂应激的不同反应机制。方法通过分子和细胞生物学方法确定Bub3和DMAP1在有丝分裂应激信号中的相互作用。研究了c-Src对DMAP1/Bub3介导的DNA甲基化和基因转录的抑制作用。分析c-Src介导的DMAP1磷酸化和体内紫杉醇活性与临床病理特征的关系。结果有丝分裂停滞诱导Ser211处p38依赖的Bub3磷酸化，促进DMAP1/Bub3相互作用。DMAP1/Bub3复合体被TAp73招募到抗凋亡基因BCL2L1的启动子上，从而介导DNA甲基化，抑制与细胞凋亡相关的基因转录。同时，在胰腺癌细胞中，DMAP1在Tyr246处被c-Src高度磷酸化，这阻碍了DMAP1/Bub3相互作用和相关的细胞活性。阻断DMAP1 pTyr-246可增强紫杉醇抑制的肿瘤生长。在临床上，DMAP1 Tyr 246的磷酸化与胰腺癌组织中c-Src活性和胰腺癌患者的预后不良相关。结论我们的研究结果揭示了Bub3在DMAP1介导的DNA甲基化中对有丝分裂应激的调节作用，并提供了DMAP1 pTyr-246与胰腺癌治疗过程中有丝分裂应激抵抗的相关性。
BackgroundChromatin modification at mitosis is closely related to transcriptional reactivation in the subsequent cell cycle. We reasoned this process is deregulated by oncogenic signals, which would contribute to mitotic stress resistance in pancreatic cancer. Here, we show DMAP1/Bub3 complex mediates mitotic stress-induced cellular apoptosis, while this effect is counteracted by c-Src in pancreatic cancer cells. Our study aims to uncover an unidentified mechanism underlying the distinct response to mitotic stress between normal cells and pancreatic cancer cells.MethodsThe interaction between Bub3 and DMAP1 upon mitotic stress signaling was determined through molecular and cell biological methods. The inhibitory effect of c-Src on DMAP1/Bub3-mediated DNA methylation and gene transcription profile was investigated. The association between c-Src-mediated DMAP1 phosphorylation and paclitaxel activity in vivo and clinicopathologic characteristics were analyzed.ResultsMitotic arrest induced p38-dependent phosphorylation of Bub3 at Ser211, which promotes DMAP1/Bub3 interaction. DMAP1/Bub3 complex is recruited by TAp73 to the promoter of anti-apoptotic geneBCL2L1, thus mediates the DNA methylation and represses gene transcription linked to cell apoptosis. Meanwhile, DMAP1 was highly phosphorylated at Tyr 246 by c-Src in pancreatic cancer cells, which impedes DMAP1/Bub3 interaction and the relevant cellular activites. Blocking DMAP1 pTyr-246 potentiates paclitaxel-inhibited tumor growth. Clinically, DMAP1 Tyr 246 phosphorylation correlates with c-Src activity in human pancreatic cancer specimens and poor prognosis in pancreatic cancer patients.ConclusionsOur findings reveal a regulatory role of Bub3 in DMAP1-mediated DNA methylation upon mitotic stress and provide the relevance of DMAP1 pTyr-246 to mitotic stress resistance during pancreatic cancer treatment.