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

Hang Liang; Qian Wang; Ding Wang; Hongwu Zheng; Dhan V Kalvakolanu; Hua Lu; Naiyan Wen; Xuyang Chen; Libo Xu; Jiaxin Ren; Baofeng Guo; Ling Zhang

doi:10.1016/j.bcp.2020.114118

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. Epub 2020 Jun 23.

Authors

Hang Liang¹, Qian Wang¹, Ding Wang¹, Hongwu Zheng², Dhan V Kalvakolanu³, Hua Lu⁴, Naiyan Wen¹, Xuyang Chen¹, Libo Xu¹, Jiaxin Ren¹, Baofeng Guo⁵, Ling Zhang⁶

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: gbf@jlu.edu.cn.
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: zhangling3@jlu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / pharmacology*
Animals
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Differentiation / drug effects*
Cell Line, Tumor
Cell Survival / drug effects
Cell Transformation, Neoplastic / drug effects
Glioma / metabolism
Glioma / pathology
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplastic Stem Cells / drug effects*
Neoplastic Stem Cells / enzymology
Neoplastic Stem Cells / pathology
Phenylenediamines / pharmacology*
RNA, Small Interfering / genetics
Signal Transduction
Smad7 Protein / metabolism*
Transforming Growth Factor beta / metabolism*
Xenograft Model Antitumor Assays

Substances

Acrylamides
Histone Deacetylase Inhibitors
Phenylenediamines
RGFP966
RNA, Small Interfering
SMAD7 protein, human
Smad7 Protein
Transforming Growth Factor beta
Histone Deacetylases
histone deacetylase 3