Differential Regulation of H3K9/H3K14 Acetylation by Small Molecules Drives Neuron-Fate-Induction of Glioma Cell

Authors

Xincheng Liu
Cui Guo
Tiandong Leng
Zhen Fan
Jialuo Mai
Jiehong Chen
Jinhai Xu
Qianyi Li
Bin Jiang
Ke Sai
Wenzhuo Yang
Jiayu Gu
Jingyi Wang
Shuxin Sun
Zhijie Chen
Yingqian Zhong
Xuanming Liang
Chaoxin Chen
Jing Cai
Yuan Lin
Jiankai Liang
Jun Hu
Guangmei Yan
Wenbo Zhu
Wei Yin

Publication Date

2-20-2023

Journal

Cell Death & Disease

Abstract

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.

Keywords

Humans, Acetylation, Histones, Lysine, Glioma, Glioblastoma, Histone Deacetylase Inhibitors, CNS cancer, Epigenetics

Comments

Supplementary Materials

PMID: 36805688