Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Anahid Ehteda; Sandy Simon; Laura Franshaw; Federico M Giorgi; Jie Liu; Swapna Joshi; Jourdin R C Rouaen; Chi Nam Ignatius Pang; Ruby Pandher; Chelsea Mayoh; Yujie Tang; Aaminah Khan; Caitlin Ung; Ornella Tolhurst; Anne Kankean; Elisha Hayden; Rebecca Lehmann; Sylvie Shen; Anjana Gopalakrishnan; Peter Trebilcock; Katerina Gurova; Andrei V Gudkov; Murray D Norris; Michelle Haber; Orazio Vittorio; Maria Tsoli; David S Ziegler

doi:10.1016/j.celrep.2021.108994

Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Cell Rep. 2021 Apr 13;35(2):108994. doi: 10.1016/j.celrep.2021.108994.

Authors

Anahid Ehteda¹, Sandy Simon¹, Laura Franshaw¹, Federico M Giorgi², Jie Liu¹, Swapna Joshi¹, Jourdin R C Rouaen¹, Chi Nam Ignatius Pang³, Ruby Pandher¹, Chelsea Mayoh⁴, Yujie Tang⁵, Aaminah Khan¹, Caitlin Ung¹, Ornella Tolhurst¹, Anne Kankean¹, Elisha Hayden¹, Rebecca Lehmann¹, Sylvie Shen¹, Anjana Gopalakrishnan¹, Peter Trebilcock¹, Katerina Gurova⁶, Andrei V Gudkov⁶, Murray D Norris⁷, Michelle Haber¹, Orazio Vittorio⁴, Maria Tsoli⁸, David S Ziegler⁹

Affiliations

¹ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
² Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
³ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
⁴ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.
⁵ State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁶ Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
⁷ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; Centre for Childhood Cancer Research, University of New South Wales, Sydney, NSW, Australia.
⁸ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia. Electronic address: mtsoli@ccia.org.au.
⁹ Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia; Kid's Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia. Electronic address: d.ziegler@unsw.edu.au.

PMID: 33852836
DOI: 10.1016/j.celrep.2021.108994

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.

Keywords: DIPG; E2F1; EZH2; H3K27M; HDAC; anticancer therapy; brainstem glioma; facilitates chromatin transcription complex; pediatric cancer; xenograft model.

Publication types

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

MeSH terms

Acetylation
Animals
Antineoplastic Agents / pharmacology*
Brain Stem Neoplasms / drug therapy*
Brain Stem Neoplasms / genetics
Brain Stem Neoplasms / mortality
Brain Stem Neoplasms / pathology
Carbazoles / pharmacology
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Child
Chromatin / chemistry
Chromatin / metabolism
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Diffuse Intrinsic Pontine Glioma / drug therapy*
Diffuse Intrinsic Pontine Glioma / genetics
Diffuse Intrinsic Pontine Glioma / mortality
Diffuse Intrinsic Pontine Glioma / pathology
Drug Synergism
E2F1 Transcription Factor / genetics
E2F1 Transcription Factor / metabolism
Epigenesis, Genetic*
Epigenome
High Mobility Group Proteins / genetics*
High Mobility Group Proteins / metabolism
Histones / antagonists & inhibitors
Histones / genetics*
Histones / metabolism
Humans
Methylation
Mice
Neuroglia / drug effects*
Neuroglia / metabolism
Neuroglia / pathology
Panobinostat / pharmacology
Primary Cell Culture
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism
Signal Transduction
Survival Analysis
Transcription Factors / genetics
Transcription Factors / metabolism
Transcriptional Elongation Factors / genetics*
Transcriptional Elongation Factors / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
CBLC137
Carbazoles
Cell Cycle Proteins
Chromatin
DNA-Binding Proteins
E2F1 Transcription Factor
E2F1 protein, human
High Mobility Group Proteins
Histones
Retinoblastoma Protein
SSRP1 protein, human
SUPT16H protein, human
TP53 protein, human
Transcription Factors
Transcriptional Elongation Factors
Tumor Suppressor Protein p53
Panobinostat