Targeting EHMT2/ G9a for cancer therapy: Progress and perspective

Jan, Suraya; Dar, Mohd Ishaq; Wani, Rubiada; Sandey, Jagjeet; Mushtaq, Iqra; Lateef, Sammar; Syed, Sajad Hussain

doi:10.1016/j.ejphar.2020.173827

Cited by 35 publications

(36 citation statements)

References 190 publications

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“…Indeed, emerging evidence suggests that PRDM12 cooperates with several proteins to regulate a critical set of genes required for the commitment of neuronal progenitors. Moreover, the mechanisms underlying G9a recruitment and function should be elucidated given the recent progress on the use of molecules targeting this histone methyltransferase for the therapy of many cancers and other human diseases [ 72 ]. Accordingly, PRDM12 is not expressed in adult normal tissues, even though its expression is re-activated in several cancer types.…”

Section: Discussionmentioning

confidence: 99%

PRDM12 in Health and Diseases

Rienzo

Zazzo

Casamassimi

et al. 2021

IJMS

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PRDM12 is a member of the PRDI-BF1 (positive regulatory domain I-binding factor 1) homologous domain (PRDM)-containing protein family, a subfamily of Kruppel-like zinc finger proteins, controlling key processes in the development of cancer. PRDM12 is expressed in a spatio-temporal manner in neuronal systems where it exerts multiple functions. PRDM12 is essential for the neurogenesis initiation and activation of a cascade of downstream pro-neuronal transcription factors in the nociceptive lineage. PRDM12 inactivation, indeed, results in a complete absence of the nociceptive lineage, which is essential for pain perception. Additionally, PRDM12 contributes to the early establishment of anorexigenic neuron identity and the maintenance of high expression levels of pro-opiomelanocortin, which impacts on the program bodyweight homeostasis. PRDMs are commonly involved in cancer, where they act as oncogenes/tumor suppressors in a “Yin and Yang” manner. PRDM12 is not usually expressed in adult normal tissues but its expression is re-activated in several cancer types. However, little information is currently available on PRDM12 expression in cancers and its mechanism of action has not been thoroughly described. In this review, we summarize the recent findings regarding PRDM12 by focusing on four main biological processes: neurogenesis, pain perception, oncogenesis and cell metabolism. Moreover, we wish to highlight the importance of future studies focusing on the PRDM12 signaling pathway(s) and its role in cancer onset and progression.

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Section: Discussionmentioning

confidence: 99%

PRDM12 in Health and Diseases

Rienzo

Zazzo

Casamassimi

et al. 2021

IJMS

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“…Compounds tested in experimental brain tumor models include molecules based on different chemical scaffolds, including diazepinquinazolin-amines, benzimidazoles, natural products of chitin, and others. [89][90][91]. UNC0638 and other inhibitors are examples of a class of substrate competitive inhibitors, which directly occupy the binding site of the histone to G9a and specifically bind the substrate site in G9a, whereas other compounds constitute a second class of agents that act as competitive inhibitors of the S-adenosyl-methionine (SAM) cofactor [89].…”

Section: Discussionmentioning

confidence: 99%

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

Souza

Freire

Jaeger

et al. 2021

IJMS

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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.

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“…G9a inhibitors have been put forward as potential anticancer agents, and research efforts have been made for the development of effective small molecule agents, based on different chemical scaffolds including diazepinquinazolin-amines, benzimidazoles, natural products of chitin, and others. [43][44][45]. UNC0638 and other inhibitors are examples of a class of substrate competitive inhibitors, which directly occupy the binding site of the histone to G9a and specifically bind the substrate site in G9a, whereas other compounds constitute a second class of agents that act as competitive inhibitors of the Sadenosyl-methionine (SAM) cofactor [43].…”

Section: Discussionmentioning

confidence: 99%

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

Souza¹,

Freire²,

Jaeger³

et al. 2021

Preprint

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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 mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), regulates changes in gene expression involved in embryonic development and differentiation of normal tissues. Overexpression of G9a has been observed in 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 multiforme (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. G9a inhibition dose-dependently reduces the viability of MB cells. Transcriptional levels of G9a are higher in MB tumors belonging to the SHH, Group 3, and Group 4, compared to Wnt tumors, and higher G9a gene expression may be a predictor of poor prognosis in patients with MB.

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Targeting EHMT2/ G9a for cancer therapy: Progress and perspective

Cited by 35 publications

References 190 publications

PRDM12 in Health and Diseases

PRDM12 in Health and Diseases

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

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

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