RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma

	RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma
	Tu, Qiu; Liu, Xiuyun; Yao, Xiaoqing; Li, Ruixue; Liu, Gaojing; Jiang, Honglv; Li, Kaiqin; Chen, Qiongfang; Huang, Xiaoyan; Chang, Qing; Xu, Guoqiang; Zhu, Hong; Shi, Peng; Zhao, Bo
	2022
发表期刊	JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
卷号	41 期号:1
摘要	Background Severe hypoxia is a prominent character of pancreatic ductal adenocarcinoma (PDAC) microenvironment. In the process of gemcitabine based chemotherapy, PDAC cells are insulted from replication stresses co-induced by hypoxia and gemcitabine. However, PDAC cells get outstanding abilities to resist to such harsh conditions and keep proliferating, causing a major obstacle for current therapy. RETSAT (Retinol Saturase) is defined as a hypoxia convergent gene recently, with high expression in PDAC hypoxic sectors. This study aimed to explore the roles of RETSAT in replication stress resistance and hypoxia adaptation in PDAC cells, and decipher the underlying mechanism. Methods The expression of RETSAT was examined in TCGA (The Cancer Genome Atlas), human pancreatic cancer microarray, clinical specimens and cell lines. Functions of RETSAT were studied by means of DNA fiber assay and comet assay in monolayer cultured PDAC cell lines, three dimensional spheroids, patient derived organoids and cell derived xenograft mouse models. Mechanism was investigated by using iPOND (isolate proteins on nascent DNA) combined with mass spectrometry, immunoprecipitation and immunoblotting. Results First, we found the converse relationship of RETSAT expression and PDAC chemotherapy. That is, PDAC patients with high RETSAT expression correlated with poor survival, while ones holding low RETSAT expression were benefitted more in Gemcitabine based chemotherapy. Second, we identified RETSAT as a novel replication fork associated protein. HIF-1 alpha signaling promotes RETSAT expression under hypoxia. Functionally, RETSAT promoted fork restarting under replication stress and maintained genomic stability. Third, we uncovered the interaction of RETSAT and R-loop unwinding helicase DDX39B. RETSAT detained DDX39B on forks to resolve R-loops, through which avoided fork damage and CHK1 initiated apoptosis. Targeting DDX39B using chemical CCT018159 sensitized PDAC cells and organoids to gemcitabine induced apoptosis, highlighting the synergetic application of CCT018159 and gemcitabine in PDAC chemotherapy. Conclusions This study identified RETSAT as a novel replication fork protein, which functions through interacting with DDX39B mediated R-loop clearance to promote fork restarting, leading to cellular resistance to replication stresses co-induced by tumor environmental hypoxia and gemcitabine in pancreatic ductal adenocarcinoma.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/13129
专题	科研部门_进化与功能基因组学（施鹏）遗传资源与进化国家重点实验室
推荐引用方式 GB/T 7714	Tu, Qiu,Liu, Xiuyun,Yao, Xiaoqing,et al. RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma[J]. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,2022,41(1).
APA	Tu, Qiu.,Liu, Xiuyun.,Yao, Xiaoqing.,Li, Ruixue.,Liu, Gaojing.,...&Zhao, Bo.(2022).RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma.JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,41(1).
MLA	Tu, Qiu,et al."RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma".JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 41.1(2022).

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