G9a Promotes Breast Cancer Recurrence Through Repression of a Pro-inflammatory Program

Mabe, Nathaniel W.; Wolery, Shayna E.; Newcomb, R.; Meingasner, Ryan C.; Vilona, Brittany A.; Lin, Chao-Chieh; Lupo, Ryan; Chi, Jen-Tsan; Alvarez, James V.

doi:10.1101/2020.01.09.900183

Cited by 5 publications

(8 citation statements)

References 91 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RNA sequencing data comparing primary and recurrent MTB;TAN-derived tumour cell lines is available online using National Center for Biotechnology Information’s Short Read Archive (SRA) under project accession number 626PRJNA505839 18 . Prognostic analysis for NRF2 gene signatures was performed using Gene expression-based Outcome for Breast cancer Online (GOBO 10 ), which uses 4 datasets (GSE1456, GSE3494, GSE6532, and GSE7390), available at http://co.bmc.lu.se/gobo/gsa.pl .…”

Section: Methodsmentioning

confidence: 99%

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism

et al. 2020

Self Cite

View full text Add to dashboard Cite

The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.

show abstract

Section: Methodsmentioning

confidence: 99%

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…We previously published RNA sequencing data comparing two primary and two recurrent tumor cell lines derived from MTB;TAN mice [5]. The log 2 fold change between the average expression of the two primary and two recurrent cell liens was calculated for each gene, and genes were ranked from largest (upregulated in recurrent tumor cells) to smallest (downregulated in recurrent tumor cells) before plotting or using for gene set enrichment analysis.…”

Section: Methodsmentioning

confidence: 99%

“…We previously published ChIP-sequencing data for primary and recurrent tumor cell lines. These ChIP-seq data were processed as described [5]. Briefly, fastq files were processed with TrimGalore [8], Bowtie [9], and the MACS2 peak-calling algorithm [10].…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Epithelial-to-mesenchymal transition activates Bcat1 expression to promote recurrent tumor growth

Fox

Alvarez

2020

Preprint

Self Cite

View full text Add to dashboard Cite

Branched-chain amino acid metabolism has emerged as a crucial regulator of tumor proliferation. In particular, the branched-chain amino acid transaminase 1 (BCAT1), which catalyzes the conversion of branched-chain amino acids to α-keto acids in the cytoplasm, has been identified as a promising therapeutic target for several different cancer types, including gliomas and leukemias. BCAT1 expression has also been associated with resistance to anti-estrogen therapy in breast cancer, suggesting a role in therapeutic resistance and tumor progression. Yet a functional role for BCAT1 in promoting breast cancer recurrence has not been described. Further, BCAT1 expression is restricted to just a few specialized tissues, such as the testes and central nervous system, and the mechanism by which it becomes transcriptionally activated in tumors that arise from tissues that do not typically express BCAT1 is unclear. Here, we report that Bcat1 is upregulated in recurrent breast tumors to promote recurrent tumor growth. We find that Bcat1 is upregulated by the epithelial-to-mesenchymal transition (EMT) in mammary epithelial cells and breast cancer cells. Finally, we analyze human tumor datasets to show that BCAT1 expression is strongly correlated with epithelial-to-mesenchymal gene signatures, suggesting that EMT is the predominant regulator of BCAT1 expression in cancer. Because EMT is associated with therapy resistance, metastasis, and tumor recurrence, these findings suggest a broad clinical potential for BCAT1 inhibition.

show abstract

“…Depletion of G9a inhibits the proliferation of CSCs in CRC, lung cancer, breast cancer, and neuronal stem cells. [ 110–112 ] Inhibition of G9a could be a significant medicinal approach to treat cancer.…”

Section: Role Of G9a In Cancer Stem Cellsmentioning

confidence: 99%

Targeting H3K9 methyltransferase G9a and its related molecule GLP as a potential therapeutic strategy for cancer

Rahman

Bazaz

Devabattula

et al. 2020

J Biochem & Molecular Tox

View full text Add to dashboard Cite

H3K9 methyltransferase (G9a) and its relevant molecule GLP are the SET domain proteins that specifically add mono, di and trimethyl groups on to the histone H3K9, which lead to the transcriptional inactivation of chromatin and reduce the expression of cancer suppressor genes, which trigger growth and progress of several cancer types. Various studies have demonstrated that overexpression of H3K9 methyltransferase G9a and GLP in different kinds of tumors, like lung, breast, bladder, colon, cervical, gastric, skin cancers, hepatocellular carcinoma and hematological malignancies. Several G9a and GLP inhibitors such as BIX‐01294, UNC0642, A‐366 and DCG066 were developed to combat various cancers; however, there is a need for more effective and less toxic compounds. The current molecular docking study suggested that the selected new compounds such as ninhydrin, naphthoquinone, cysteamine and disulfide cysteamine could be suitable molecules as a G9a and GLP inhibitors. Furthermore, detailed cell based and preclinical animal studies are required to confirm their properties. In the current review, we discussed the role of G9a and GLP mediated epigenetic regulation in the cancers. A thorough literature review was done related to G9a and GLP. The databases used extensively for retrieval of information were PubMed, Medline, Scopus and Science‐direct. Further, molecular docking was performed using Maestro Schrodinger version 9.2 software to investigate the binding profile of compounds with Human G9a HMT (PDB ID: 3FPD, 3RJW) and Human GLP MT (PDB ID: 6MBO, 6MBP).

show abstract

G9a Promotes Breast Cancer Recurrence Through Repression of a Pro-inflammatory Program

Cited by 5 publications

References 91 publications

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism

Epithelial-to-mesenchymal transition activates Bcat1 expression to promote recurrent tumor growth

Targeting H3K9 methyltransferase G9a and its related molecule GLP as a potential therapeutic strategy for cancer

Contact Info

Product

Resources

About