RGFP966, a histone deacetylase 3 inhibitor, promotes glioma stem cell differentiation by blocking TGF-β signaling via SMAD7

被引：11
|
作者：
Liang, Hang [1 ,2 ]
Wang, Qian [1 ,2 ]
Wang, Ding [1 ,2 ]
Zheng, Hongwu [3 ]
Kalvakolanu, Dhan, V [4 ]
Lu, Hua [5 ]
Wen, Naiyan [1 ,2 ]
Chen, Xuyang [1 ,2 ]
Xu, Libo [1 ,2 ]
Ren, Jiaxin [1 ,2 ]
Guo, Baofeng [6 ]
Zhang, Ling [1 ,2 ]
机构：
[1] Jilin Univ, Minist Educ, Key Lab Pathobiol, Changchun 130021, Peoples R China
[2] Jilin Univ, Dept Pathophysiol, Coll Basic Med Sci, Changchun 130021, Peoples R China
[3] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY 10065 USA
[4] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Greenebaum NCI Comprehens Canc Ctr, Baltimore, MD 21201 USA
[5] Tulane Univ, Sch Med, Dept Biochem & Mol Biol, Tulane Canc Ctr, 1430 Tulane Ave, New Orleans, LA 70112 USA
[6] Jilin Univ, China Japan Union Hosp, Dept Plast Surg, Changchun 130033, Peoples R China
来源：
BIOCHEMICAL PHARMACOLOGY | 2020年 / 180卷
基金：
中国国家自然科学基金;
关键词：
Glioma stem cells; Differentiation; HDAC3; TGF-beta; SMAD7; Growth arrest; THERAPEUTIC TARGET; ACETYLATION; SUPPRESSOR; EXPRESSION; CANCER;
D O I：
10.1016/j.bcp.2020.114118
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
Glioma stem cells (GSC) play a major role in drug resistance and tumor recurrence. Using a genetic screen with a set of shRNAs that can target chromatin regulators in a GSC model, we have HDAC3 as a major negative regulator of GSC differentiation. Inhibition of HDAC3 using a pharmacological inhibitor or a siRNA led to the induction of GSC differentiation into astrocytes. Consequently, HDAC3-inhibition also caused a strong reduction of tumor-promoting and self-renewal capabilities of GSCs. These phenotypes were highly associated with an increased acetylation of SMAD7, which protected its ubiquitination. SMAD7 inhibits a TGF-beta signaling axis that is required for maintaining stemness. These results demonstrate that HDAC3 appears to be a proper target in anti-glioma therapy.
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收藏
页数：13
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