期刊
BIOCHEMICAL PHARMACOLOGY
卷 180, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2020.114118
关键词
Glioma stem cells; Differentiation; HDAC3; TGF-beta; SMAD7; Growth arrest
资金
- Fundamental Research Funds for the Central Universities, JLU
- National Natural Science Foundation of China [81773217]
- Research Fund of Jilin Provincial Science and Technology Department [20190701065GH, 20200404120YY]
- Jilin Province Health Technology Innovation Project [2019J030]
- Cigarette Restitution Funds of the University of Maryland Greenebaum NCI comprehensive Cancer Center
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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