EHMT2/G9a As an Epigenetic Target in Pediatric and Adult Brain Tumors

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Oct 23

PMID 34681949

Citations 7

Authors

Barbara Kunzler Souza

Natalia Hogetop Freire

Mariane Jaeger

Caroline Brunetto de Farias

Algemir L Brunetto

Andre T Brunetto

Rafael Roesler

Affiliations

Soon will be listed here.

Abstract

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

Citing Articles

Neuroendocrine transdifferentiation in human cancer: molecular mechanisms and therapeutic targets.

Jiang J, Han D, Wang J, Wen W, Zhang R, Qin W MedComm (2020). 2024; 5(10):e761.

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G9a in Cancer: Mechanisms, Therapeutic Advancements, and Clinical Implications.

Ni Y, Shi M, Liu L, Lin D, Zeng H, Ong C Cancers (Basel). 2024; 16(12).

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Histone Methyltransferases G9a/ and GLP/ Are Associated with Cell Viability and Poorer Prognosis in Neuroblastoma and Ewing Sarcoma.

Souza B, Freire N, Monteiro T, Herlinger A, Jaeger M, Dalmolin M Int J Mol Sci. 2023; 24(20).

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De novo methylation of histone H3K23 by the methyltransferases EHMT1/GLP and EHMT2/G9a.

Vinson D, Stephens K, OMeally R, Bhat S, Dancy B, Cole R Epigenetics Chromatin. 2022; 15(1):36.

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DNA Methylation Changes in Autologous Hematopoietic Stem Cell Transplant Patients.

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References

Ghildiyal R, Sen E . Concerted action of histone methyltransferases G9a and PRMT-1 regulates PGC-1α-RIG-I axis in IFNγ treated glioma cells. Cytokine. 2016; 89:185-193. DOI: 10.1016/j.cyto.2015.12.008. View

Wiegel B, Harris T, Edwards M, Smith R, Azzarelli B . MR of intracranial neuroblastoma with dural sinus invasion and distant metastases. AJNR Am J Neuroradiol. 1991; 12(6):1198-200. PMC: 8331460. View

Nor C, Sassi F, de Farias C, Schwartsmann G, Abujamra A, Lenz G . The histone deacetylase inhibitor sodium butyrate promotes cell death and differentiation and reduces neurosphere formation in human medulloblastoma cells. Mol Neurobiol. 2013; 48(3):533-43. DOI: 10.1007/s12035-013-8441-7. View

Almeida V, Vieira I, Buendia M, Brunetto A, Gregianin L, Brunetto A . Combined Treatments with a Retinoid Receptor Agonist and Epigenetic Modulators in Human Neuroblastoma Cells. Mol Neurobiol. 2016; 54(10):7610-7619. DOI: 10.1007/s12035-016-0250-3. View

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

Milner C, Campbell R . The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats. Biochem J. 1993; 290 ( Pt 3):811-8. PMC: 1132354. DOI: 10.1042/bj2900811. View

Cavalli F, Remke M, Rampasek L, Peacock J, Shih D, Luu B . Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell. 2017; 31(6):737-754.e6. PMC: 6163053. DOI: 10.1016/j.ccell.2017.05.005. View

Soumyanarayanan U, Dymock B . Recently discovered EZH2 and EHMT2 (G9a) inhibitors. Future Med Chem. 2016; 8(13):1635-54. DOI: 10.4155/fmc-2016-0096. View

Ramaswamy V, Remke M, Bouffet E, Bailey S, Clifford S, Doz F . Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol. 2016; 131(6):821-31. PMC: 4867119. DOI: 10.1007/s00401-016-1569-6. View

10.

Egger G, Liang G, Aparicio A, Jones P . Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004; 429(6990):457-63. DOI: 10.1038/nature02625. View

11.

Gursoy-Yuzugullu O, Carman C, Serafim R, Myronakis M, Valente V, Price B . Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity. Oncotarget. 2017; 8(15):24518-24532. PMC: 5421867. DOI: 10.18632/oncotarget.15543. View

12.

Shankar S, Bahirvani A, Rao V, Bharathy N, Ow J, Taneja R . G9a, a multipotent regulator of gene expression. Epigenetics. 2012; 8(1):16-22. PMC: 3549875. DOI: 10.4161/epi.23331. View

13.

Chen M, Hua K, Kao H, Chi C, Wei L, Johansson G . H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 2010; 70(20):7830-40. DOI: 10.1158/0008-5472.CAN-10-0833. View

14.

Wu G, Diaz A, Paugh B, Rankin S, Ju B, Li Y . The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet. 2014; 46(5):444-450. PMC: 4056452. DOI: 10.1038/ng.2938. View

15.

Bao L, Chen Y, Lai H, Wu S, Wang J, Hatanpaa K . Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration. Nucleic Acids Res. 2018; 46(13):6576-6591. PMC: 6061882. DOI: 10.1093/nar/gky449. View

16.

Ciechomska I, Jayaprakash C, Maleszewska M, Kaminska B . Histone Modifying Enzymes and Chromatin Modifiers in Glioma Pathobiology and Therapy Responses. Adv Exp Med Biol. 2020; 1202:259-279. DOI: 10.1007/978-3-030-30651-9_13. View

17.

Chandar Charles M, Hsieh H, Coumar M . Delineating the active site architecture of G9a lysine methyltransferase through substrate and inhibitor binding mode analysis: a molecular dynamics study. J Biomol Struct Dyn. 2018; 37(10):2581-2592. DOI: 10.1080/07391102.2018.1491422. View

18.

Li Q, Dong C, Cui J, Wang Y, Hong X . Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme. J Exp Clin Cancer Res. 2018; 37(1):265. PMC: 6208043. DOI: 10.1186/s13046-018-0941-x. View

19.

von Bueren A, Kortmann R, von Hoff K, Friedrich C, Mynarek M, Muller K . Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters. J Clin Oncol. 2016; 34(34):4151-4160. DOI: 10.1200/JCO.2016.67.2428. View

20.

Northcott P, Robinson G, Kratz C, Mabbott D, Pomeroy S, Clifford S . Medulloblastoma. Nat Rev Dis Primers. 2019; 5(1):11. DOI: 10.1038/s41572-019-0063-6. View