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姜海

[email protected] 

https://www.sibcb.ac.cn/PI.asp?id=140 

中科院上海生化细胞研究所 研究员       

主题报告

2018年09月19日17:15-17:25 主题报告：

UTX functions as an escape from X-inactivation tumor-suppressor in B cell lymphoma

Comparing to females, males are more prone to develop cancer. To explain such difference, several candidates for ‘escape from X-inactivation tumor-suppressor’ (EXITS) were recently proposed. It is proposed that certain tumor suppressors on X chromsome escape from X-inactivation. Therefore females exhibit two functional copies of such tumor suppressor, and are therefore better protected against cancer than males. One of such EXITS candidate is UTX, which is an epigenetic regulator commonly mutated or deleted in human cancers. Combining tissue-specific UTX knockout mice and mouse models of lymphoma, we interrogated the role of UTX as a potential EXITS. Our results show that UTX copy number clearly impacted tumor development, which strongly supports the EXITS theory. Importantly, UTX deletion not only accelerates lymphomagenesis, it also strongly promotes tumor progression. UTX deficient tumor displayed significantly enhanced brain dissemination and blood vessel formation. We also studied the potential weakness associated with UTX deficiency and showed that UTX deficiency renders lymphoma sensitive to cytarabine treatment. Taken together, these data highlight UTX loss’s profound impacts on tumor initiation, progression and drug response.

科研成果

代表性文章：

1. Nat Commun. 2018 Jul 13;9(1):2720. doi: 10.1038/s41467-018-05084-w.

UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma.

Li X, Zhang Y, Zheng L, Liu M, Chen CD, Jiang H.

To explain the excess cancer rate in males, several candidates for ‘escape from X-inactivation tumor-suppressor’ (EXITS) were recently identified. In this report we provide direct experimental evidence supporting UTX’s role as an EXITS gene. Using a mouse lymphoma model, we show clear dosage effect of UTX copy number during tumorigenesis, which strongly supports the EXITS theory. Importantly, UTX deletion not only accelerates lymphomagenesis, it also strongly promotes tumor progression. UTX knockout tumors are more aggressiveness, showing enhanced brain dissemination and formation of blood vessels. Efnb1 is overexpressed in UTX KO tumors and can lead to such phenotypes. In human patients, lymphomas with low UTX expression also express high levels of Efnb1, and cause significantly poor survival. Lastly, we show that UTX deficiency renders lymphoma sensitive to cytarabine treatment. Taken together, these data highlight UTX loss’s profound impacts on tumor initiation, progression and drug response.

2. EMBO Mol Med. 2015 Apr;7(4):438-49. doi: 10.15252/emmm.201404580.

A DNA/HDAC dual-targeting drug with significantly enhanced anticancer potency.

Liu C, Ding H, Li X, Pallasch CP, Hong L, Guo D, Chen Y, Wang D, Wang W, Wang Y, Hemann MT, Jiang H.

Genotoxic drugs constitute a major treatment modality for human cancers; however, cancer cells'intrinsic DNA repair capability often increases the threshold of lethality and renders these drugs ineffective. The emerging roles of HDACs in DNA repair provide new opportunities for improving traditional genotoxic drugs. Here, we report the development and characterization of CY190602, a novel bendamustine-derived drug with significantly enhanced anticancer potency. We show that CY190602's enhanced potency can be attributed to its newly gained ability to inhibit HDACs. Using this novel DNA/HDAC dual-targeting drug as a tool, we further explored HDAC's role in DNA repair. We found that HDAC activities are essential for the expression of several genes involved in DNA synthesis and repair, including TYMS, Tip60, CBP, EP300, and MSL1. Importantly, CY190602, the first-in-class example of such DNA/HDAC dual-targeting drugs, exhibited significantly enhanced anticancer activity in vitro and in vivo. These findings provide rationales for incorporating HDAC inhibitory moieties into genotoxic drugs, so as to overcome the repair capacity of cancer cells. Systematic development of similar DNA/HDAC dual-targeting drugs may represent a novel opportunity for improving cancer therapy.

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