G9a, a multipotent regulator of gene expression

Shankar, Shilpa Rani; Bahirvani, Avinash Govind; Rao, Vinay Kumar; Bharathy, Narendra; Ow, Jin Rong; Taneja, Reshma

doi:10.4161/epi.23331

Cited by 149 publications

(134 citation statements)

References 67 publications

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“…Using enzymatic activity, G9a cooperates with different transcription factors for maintaining physical functions (47). Here, we found that the binding sites of ATF4, which have been shown to contribute to GCLC upregulation (40), are identical to the pattern of G9a-mediated H3K9me1 on the GCLC promoter.…”

Section: Discussionmentioning

confidence: 50%

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Liu

Hua

et al. 2017

Molecular Cancer Therapeutics

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Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatinresistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC.

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Section: Discussionmentioning

confidence: 50%

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Liu

Hua

et al. 2017

Molecular Cancer Therapeutics

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“…The H3K9me2 mark is unique compared with some other histone modifications because of its broad regional deposition (72). It has been proposed that G9a target specificity is determined by multiple interactions with chromatin or sequence-specific DNA-binding molecules (6,8). It would be interesting to determine whether G9a binding mediates chromatin looping to allow its interaction with multiple sites in the genome from a localized domain.…”

Section: Discussionmentioning

confidence: 99%

A Role for Widely Interspaced Zinc Finger (WIZ) in Retention of the G9a Methyltransferase on Chromatin

Simon

Parker

Liu

et al. 2015

Journal of Biological Chemistry

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Background: G9a-GLP lysine methyltransferases mono-and di-methylate histone H3 lysine 9 (H3K9me2). Results: Widely interspaced zinc finger (WIZ) regulates H3K9me2 levels through a mechanism that involves retention of G9a on chromatin. Conclusion:The G9a-GLP-WIZ complex has unique functions when bound to chromatin that are independent of the H3K9me2 mark. Significance: Combining pharmacologic and genetic manipulations is essential to any translational hypotheses related to G9a function.

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“…The longest one resembles more the structure of the mG9a protein, which is the product of NG36-G9a transcript (Fig. 1C and Shankar SR, et al 2013). Previous studies have revealed differences in the sub-cellular distribution of the NG36-G9a and G9a proteins.…”

Section: Correlation Between P53 and Hg9a Expression Is Associated Wimentioning

confidence: 92%

“…Furthermore, G9a and GLP methylate non-histone substrates, among them CEBP β (K39), WIZ (K305), ACINUS (K654), G9a (automethylation), MyoD (K104) CDYL1 (K135), HDAC1, DNMT1, KLF12 25 , and reptin (K67) 21,26 , and p53 (K373) 27 .…”

mentioning

confidence: 99%

“…Notwithstanding the current consensus on the role of G9a in regulation of transcriptional activity as a transcriptional co-repressor, recent studies have challenged this view by showing that G9a also positively regulates gene expression and thus acts as a co-activator 25,[30][31][32][33] . In this respect, G9a was recently reported as a transcriptional coactivator for Glucocorticoid Receptor (GR), by forming a molecular scaffold to recruit and facilitate binding of other co-activating proteins including GRIP1, CARM1 and p300 32,34 .…”

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confidence: 99%

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Human EHMT2/G9a activates p53 through methylation-independent mechanism

et al. 2016

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ABSTRACTp53 is a critical tumor suppressor in humans. It functions mostly as a transcriptional factor and its activity is regulated by numerous post-translational modifications. Among different covalent modifications found on p53 the most controversial one is lysine methylation. We found that human G9a (hG9a) unlike its mouse orthologue (mG9a) potently stimulated p53 transcriptional activity. Both ectopic and endogenous hG9a augmented p53-dependent transcription of pro-apoptotic genes, including Bax and PUMA, resulting in enhanced apoptosis and reduced colony formation. Significantly, siRNA-mediated knockdown of hG9a attenuated p53-dependent activation of PUMA. On the molecular level, hG9a interacted with histone acetyltransferase, p300/CBP, resulting in increased histone acetylation at the promoter of PUMA. The bioinformatics data substantiated our findings showing that positive correlation between G9a and p53 expression is associated with better survival of lung cancer patients. Collectively, this study demonstrates that depending on the cellular and organismal context, orthologous proteins may exert both overlapping and opposing functions.Furthermore, this finding has important ramifications on the use of G9a inhibitors in combination with genotoxic drugs to treat p53-positive tumors.3

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G9a, a multipotent regulator of gene expression

Cited by 149 publications

References 67 publications

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

A Role for Widely Interspaced Zinc Finger (WIZ) in Retention of the G9a Methyltransferase on Chromatin

Human EHMT2/G9a activates p53 through methylation-independent mechanism

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