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Molecular Cancer
Published in: Molecular Cancer 1/2018

Open Access 01-12-2018 | Research

C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer

Authors: Jingjie Li, Bin Hu, Ting Wang, Wenhua Huang, Chunmin Ma, Qin Zhao, Lingang Zhuo, Tao Zhang, Yuhui Jiang

Published in: Molecular Cancer | Issue 1/2018

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Abstract

Background

Chromatin 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.

Methods

The 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.

Results

Mitotic 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 gene BCL2L1, 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.

Conclusions

Our 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.
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Metadata
Title
C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer
Authors
Jingjie Li
Bin Hu
Ting Wang
Wenhua Huang
Chunmin Ma
Qin Zhao
Lingang Zhuo
Tao Zhang
Yuhui Jiang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2018
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0919-5

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