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

  • Biochem Pharmacol. 2020 Oct;180:114118. doi: 10.1016/j.bcp.2020.114118.
Hang Liang  1 ,  Qian Wang  1 ,  Ding Wang  1 ,  Hongwu Zheng  2 ,  Dhan V Kalvakolanu  3 ,  Hua Lu  4 ,  Naiyan Wen  1 ,  Xuyang Chen  1 ,  Libo Xu  1 ,  Jiaxin Ren  1 ,  Baofeng Guo  5 ,  Ling Zhang  6
Affiliations
  • 1. Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, PR China.
  • 2. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 3. Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology University of Maryland School Medicine, Baltimore, MD, USA.
  • 4. Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
  • 5. Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China. Electronic address: [email protected].
  • 6. Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, PR China. Electronic address: [email protected].
PMID: 32585142 DOI: 10.1016/j.bcp.2020.114118
Abstract

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-β signaling axis that is required for maintaining stemness. These results demonstrate that HDAC3 appears to be a proper target in anti-glioma therapy.

Keywords
Differentiation; Glioma stem cells; Growth arrest; HDAC3; SMAD7; TGF-β.
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