Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma

Robert Siddaway; Laura Canty; Sanja Pajovic; Scott Milos; Etienne Coyaud; Stefanie-Grace Sbergio; Arun Kumaran Vadivel Anguraj; Evan Lubanszky; Hwa Young Yun; Alessia Portante; Sheyenne Carette; Cunjie Zhang; Michael F Moran; Brian Raught; Eric I Campos; Cynthia Hawkins

doi:10.1007/s00401-022-02489-2

Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma

Acta Neuropathol. 2022 Nov;144(5):1027-1048. doi: 10.1007/s00401-022-02489-2. Epub 2022 Sep 7.

Authors

Robert Siddaway^{1

2

3}, Laura Canty^{1

2}, Sanja Pajovic^{1

2}, Scott Milos^{1

2}, Etienne Coyaud^{4

5}, Stefanie-Grace Sbergio^{1

6}, Arun Kumaran Vadivel Anguraj^{1

2}, Evan Lubanszky^{1

2

6}, Hwa Young Yun^{6

7}, Alessia Portante^{1

2

6}, Sheyenne Carette^{1

2}, Cunjie Zhang², Michael F Moran^{2

8}, Brian Raught^{4

9}, Eric I Campos^{7

8}, Cynthia Hawkins^{10

11

12

13

14}

Affiliations

¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
² Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
³ Division of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
⁴ Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON, M5G 1L7, Canada.
⁵ Université de Lille, Inserm, CHU Lille, U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, 59000, Lille, France.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁷ Genetics & Genome Biology Program, Hospital for Sick Children, 686 Bay Street, Toronto, ON, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁰ The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada. cynthia.hawkins@sickkids.ca.
¹¹ Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca.
¹² Division of Pathology, Hospital for Sick Children, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca.
¹³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca.
¹⁴ Department of Paediatric Laboratory Medicine, Arthur and Sonia Labatt Brain Tumour Research Centre, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. cynthia.hawkins@sickkids.ca.

Abstract

Histone H3 mutations at amino acids 27 (H3K27M) and 34 (H3G34R) are recurrent drivers of pediatric-type high-grade glioma (pHGG). H3K27M mutations lead to global disruption of H3K27me3 through dominant negative PRC2 inhibition, while H3G34R mutations lead to local losses of H3K36me3 through inhibition of SETD2. However, their broader oncogenic mechanisms remain unclear. We characterized the H3.1K27M, H3.3K27M and H3.3G34R interactomes, finding that H3K27M is associated with epigenetic and transcription factor changes; in contrast H3G34R removes a break on cryptic transcription, limits DNA methyltransferase access, and alters mitochondrial metabolism. All 3 mutants had altered interactions with DNA repair proteins and H3K9 methyltransferases. H3K9me3 was reduced in H3K27M-containing nucleosomes, and cis-H3K9 methylation was required for H3K27M to exert its effect on global H3K27me3. H3K9 methyltransferase inhibition was lethal to H3.1K27M, H3.3K27M and H3.3G34R pHGG cells, underscoring the importance of H3K9 methylation for oncohistone-mutant gliomas and suggesting it as an attractive therapeutic target.

Keywords: H3G34R; H3K27M; H3K9 methylation; pHGG.

Publication types

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

MeSH terms

Amino Acids / genetics
Child
DNA
Glioma* / genetics
Glioma* / metabolism
Histones* / genetics
Humans
Mutation / genetics
Nucleosomes
Transcription Factors / genetics

Substances

Amino Acids
Histones
Nucleosomes
Transcription Factors
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding