KDM4 Inhibition Targets Breast Cancer Stem–like Cells

Metzger, Eric; Stepputtis, Stella S.; Strietz, Juliane; Preca, Bogdan Tiberius; Urban, Sylvia; Willmann, Dominica; Allen, Anita L.; Zenk, Fides; Iovino, Nicola; Bronsert, Peter; Proske, Amelie; Follo, Marie; Boerries, Melanie; Stickeler, Elmar; Xu, Jiangchun; Wallace, Michael B.; Stafford, Jeffrey A.; Kanouni, Toufike; Maurer, Jochen; Schüle, Roland

doi:10.1158/0008-5472.can-17-1754

Cited by 80 publications

(108 citation statements)

References 35 publications

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“…2E, top: KDM4A in blue and H3K9me3 in black). These observations were consistent with the previous analyses that noted that KDM4A occupied the EGFR promoter region (40), which occurs within this larger binding domain that we have identified. In addition to promoting copy gains, KDM4A overexpression also increased EGFR transcripts as determined by both RNA sequencing and quantitative RT-PCR ( Fig.…”

Section: Kdm4a Overexpression Promotes Egfr Copy Number Gainssupporting

confidence: 93%

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Histone Lysine Methylation Dynamics ControlEGFRDNA Copy-Number Amplification

et al. 2020

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Acquired chromosomal DNA copy gains are a feature of many tumors; however, the mechanisms that underpin oncogene amplifi cation are poorly understood. Recent studies have begun to uncover the importance of epigenetic states and histone lysine methyltransferases (KMT) and demethylases (KDM) in regulating transient site-specifi c DNA copy-number gains (TSSG). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylation balance to control extrachromosomal amplifi cation of the EGFR oncogene. This study further establishes that cellular signals (hypoxia and EGF) are able to directly promote EGFR amplifi cation through modulation of the enzymes controlling EGFR copy gains. Moreover, we demonstrate that chemical inhibitors targeting specifi c KMTs and KDMs are able to promote or block extrachromosomal EGFR amplifi cation, which identifi es potential therapeutic strategies for controlling EGFR copy-number heterogeneity in cancer, and, in turn, drug response. SIGNIFICANCE: This study identifi es a network of epigenetic factors and cellular signals that directly control EGFR DNA amplifi cation. We demonstrate that chemical inhibitors targeting enzymes controlling this amplifi cation can be used to rheostat EGFR copy number, which uncovers therapeutic opportunities for controlling EGFR DNA amplifi cation heterogeneity and the associated drug response.

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Section: Kdm4a Overexpression Promotes Egfr Copy Number Gainssupporting

confidence: 93%

“…Consistent with these findings, analysis of available KDM4A ChIP-seq data (40) revealed that KDM4A was enriched across the EGFR locus between the H3K9me3 blocks (1.6 Mb; Fig. 2E, top: KDM4A in blue and H3K9me3 in black).…”

Section: Kdm4a Overexpression Promotes Egfr Copy Number Gainssupporting

confidence: 74%

Histone Lysine Methylation Dynamics ControlEGFRDNA Copy-Number Amplification

et al. 2020

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“…Convincing documents demonstrated that histone demethylases involve in different cellular procedures such as carcinogenesis, cell fate selection, and cell differentiation [120][121][122]. Currently, the increasing trend of documents showed the essential contribution of histone demethylases such as JARID1, KDM4, LSD1, KDM6B, KDM6A, KMD3, KDM5, and Jumonji domain-consisting of protein 6 (JMJD6) to the cancer stem cell phenotype in several kinds of cancers [61,[123][124][125][126][127][128][129][130]. JMJD6 has been represented as a new molecular modulator of OCSCs [61].…”

Section: Epigenetic Regulators and Oral Cancer Stem Cells Histone Demmentioning

confidence: 99%

Cancer stem cells and oral cancer: insights into molecular mechanisms and therapeutic approaches

2020

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Cancer stem cells (CSCs) have been identified as a little population of cancer cells, which have features as the same as the cells normal stem cells. There is enough knowledge of the CSCs responsibility for metastasis, medicine resistance, and cancer outbreak. Therefore, CSCs control possibly provides an efficient treatment intervention inhibiting tumor growth and invasion. In spite of the significance of targeting CSCs in treating cancer, few study comprehensively explored the nature of oral CSCs. It has been showed that oral CSCs are able to contribute to oral cancer progression though activation/inhibition a sequences of cellular and molecular pathways (microRNA network, histone modifications and calcium regulation). Hence, more understanding about the properties of oral cancers and their behaviors will help us to develop new therapeutic platforms. Head and neck CSCs remain a viable and intriguing option for targeted therapy. Multiple investigations suggested the major contribution of the CSCs to the metastasis, tumorigenesis, and resistance to the new therapeutic regimes. Therefore, experts in the field are examining the encouraging targeted therapeutic choices. In spite of the advancements, there are not enough information in this area and thus a magic bullet for targeting and eliminating the CSCs deviated us. Hence, additional investigations on the combined therapies against the head and neck CSCs could offer considerable achievements. The present research is a review of the recent information on oral CSCs, and focused on current advancements in new signaling pathways contributed to their stemness regulation. Moreover, we highlighted various therapeutic approaches against oral CSCs.

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“…This model is completed by the postulated intra‐tumour hierarchy and cancer stem cells (CSCs) . It remains to be explored whether Tspan8 may change the tumourigenic properties of breast cancer CSCs; however, preliminary tests demonstrated that TSPAN8 is not expressed in cultures of the breast cancer stem‐like cells (data not shown) . Further investigation will be required to understand the molecular mechanisms of TSPAN8 up‐regulation in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Tspan8 is expressed in breast cancer and regulates E‐cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles

Voglstaetter

Thomsen

Nouvel

et al. 2019

The Journal of Pathology

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Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8+ tumours formed multiple liver and spleen metastases, while Tspan8− tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up‐regulation of E‐cadherin and down‐regulation of Twist, p120‐catenin, and β‐catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal–epithelial transition. Furthermore, Tspan8+ cells exhibited enhanced cell–cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several‐fold increase in EV number in cell culture and the circulation of tumour‐bearing animals. We observed increased protein levels of E‐cadherin and p120‐catenin in these EVs; furthermore, Tspan8 and p120‐catenin were co‐immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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KDM4 Inhibition Targets Breast Cancer Stem–like Cells

Cited by 80 publications

References 35 publications

Histone Lysine Methylation Dynamics ControlEGFRDNA Copy-Number Amplification

Histone Lysine Methylation Dynamics ControlEGFRDNA Copy-Number Amplification

Cancer stem cells and oral cancer: insights into molecular mechanisms and therapeutic approaches

Tspan8 is expressed in breast cancer and regulates E‐cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles

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