An epigenetic screening determines BET proteins as targets to suppress self-renewal and tumorigenicity in canine mammary cancer cells

Xavier, Pedro Luiz Porfírio; Cordeiro, Yonara de Gouveia; Pires, Pedro Ratto Lisboa; Saranholi, Bruno H.; Silva, Edson R.; Müller, Susanne; Fukumasu, Heidge

doi:10.1038/s41598-019-53915-7

Cited by 11 publications

(15 citation statements)

References 74 publications

(84 reference statements)

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“…Recently, we observed that the inhibition of bromodomain and extraterminal (BET) family of proteins, an epigenetic reader of histone acetylation, using (+)-JQ1, is a promising strategy to inhibit self-renewal and tumorigenicity in CMC cells using 3D in vitro models. Low concentrations of (+)-JQ1 inhibited tumorsphere and colony formation and were able to downregulate important genes associated with selfrenewal pathways including WNT, NOTCH, Hedgehog, and PI3K/AKT/mTOR (Xavier et al, 2019). These results strongly indicated that BET inhibition modulates malignant phenotypes such as self-renewal and could directly impact tumorigenic cells such as cancer stem cells (CSCs) in CMC cells.…”

Section: Open Accessmentioning

confidence: 83%

Stemness inhibition by (+)-JQ1 in canine and human mammary cancer cells revealed by machine learning

Marção

Müller²,

Xavier³

et al. 2022

Front. Drug. Discov.

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Stemness is a phenotype associated with cancer initiation and progression, malignancy, and therapeutic resistance, exhibiting particular molecular signatures. Targeting stemness has been proposed as a promising strategy against breast cancer stem cells that can play a key role in breast cancer progression, metastasis, and multiple drug resistance. Here, using a previously published one-class logistic regression machine learning algorithm (OCLR) built on pluripotent stem cells to predict stemness in human cancer samples, we provide the stemness index (mRNAsi) of different canine non-tumor and mammary cancer cells. Then, we confirmed that inhibition of BET proteins by (+)-JQ1 reduces stemness in a high mRNAsi canine cancer cell. Furthermore, using public data, we observed that (+)-JQ1 can also decrease stemness in human triple-negative breast cancer cells. Our work suggests that mRNAsi can be used to estimate stemness in different species and confirm epigenetic modulation by BET inhibition as a promising strategy for modulating the stemness phenotype in canine and human mammary cancer cells.

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Section: Open Accessmentioning

confidence: 83%

Stemness inhibition by (+)-JQ1 in canine and human mammary cancer cells revealed by machine learning

Marção

Müller²,

Xavier³

et al. 2022

Front. Drug. Discov.

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“…We observed three inhibitors inducing significant reduction of cell viability in CMCs including (+)-JQ1 (BET family inhibitor), NVS-CECR2-1 (CECR2 inhibitor), and UNC1999 (EZH2/1 inhibitor). Furthermore, BET inhibition by (+)-JQ1 was very efficient to inhibit CMCs colony and tumorsphere formation, demonstrating an effect on tumorigenicity and self-renewal ( Figure 3) (222). Inhibition of SET methyltransferase by shRNA and FTY720, reported to directly interact with SET proteins, suppressed cell proliferation, colony formation, and in vivo tumor growth of canine mammary and osteosarcoma cell lines.…”

Section: Alternative Epigenetic Targetsmentioning

confidence: 91%

“…The (+)-JQ1 (BET family inhibitor), NVS-CECR2-1 (CECR2 inhibitor), and UNC1999 (EZH2/1 inhibitor) decreased cell viability of CF41.Mg canine mammary cancer cell line. Furthermore, (+)-JQ1 exhibits a strong impact on colony and tumorspheres formation, demonstrating effects on tumorigenicity and self-renewal phenotypes (222). canine mammary cancer cells, activating endoplasmic reticulum stress pathway in these cells (225).…”

Section: Alternative Epigenetic Targetsmentioning

confidence: 99%

Epigenetic Mechanisms in Canine Cancer

2020

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A plethora of data has highlighted the role of epigenetics in the development of cancer. Initiation and progression of different cancer types are associated with a variety of changes of epigenetic mechanisms, including aberrant DNA methylation, histone modifications, and miRNA expression. At the same time, advances in the available epigenetic tools allow to investigate and reverse these epigenetic changes and form the basis for the development of anticancer drugs in human oncology. Although human and canine cancer shares several common features, only recently that studies emerged investigating the epigenetic landscape in canine cancer and applying epigenetic modulators to canine cancer. This review focuses on the existing studies involving epigenetic changes in different types of canine cancer and the use of small-molecule inhibitors in canine cancer cells.

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“…Mammary cancer cell lines were validated previously by global gene expression 8,11 and by attesting the origin of cell lines by amplification and sequencing of fragments from cytochrome oxidase I (COI) and 16S 11 …”

Section: Methodsmentioning

confidence: 99%

Oncolytic effect of Newcastle disease virus is attributed to interferon regulation in canine mammary cancer cell lines

Santos

Xavier

Pires

et al. 2021

Vet Comparative Oncology

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Canine mammary carcinoma (CMC) is one of the major health threats in dogs. The oncolytic virotherapy is a promising strategy to treat canine as well as human cancer patients with non‐pathogenic replicating viruses. Here, we evaluated the antitumor activity of one lentogenic, non‐lytic Newcastle disease virus (NDV) LaSota strain expressing GFP (NDV‐GFP) on five different CMCs and one non‐tumorigenic cell line, regarding cell viability, cell death, selectivity index, morphology, global and target gene expression analysis. As evidenced by the selectivity index, all CMC cell lines were more susceptible to NDV‐GFP in comparison with the non‐tumorigenic cells (~3.1× to ~78.7×). In addition, the oncolytic effect of NDV‐GFP was more evident in more malignant CMC cells. Also, we observed an inverse association of the IFN pathway expression and the susceptibility to NDV. The downregulated genes in NDV‐GFP‐sensitive cells were functionally enriched for antiviral mechanisms by interferon and immune system pathways, demonstrating that these mechanisms are the most prominent for oncolysis by NDV. To our knowledge, this is the first description of oncolysis by an NDV strain in canine mammary cancer cells. We also demonstrated specific molecular pathways related to NDV susceptibility in these cancer cells, opening the possibility to use NDV as a therapeutic‐targeted option for more malignant CMCs. Therefore, these results urge for more studies using oncolytic NDVs, especially considering genetic editing to improve efficacy in dogs.

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An epigenetic screening determines BET proteins as targets to suppress self-renewal and tumorigenicity in canine mammary cancer cells

Cited by 11 publications

References 74 publications

Stemness inhibition by (+)-JQ1 in canine and human mammary cancer cells revealed by machine learning

Stemness inhibition by (+)-JQ1 in canine and human mammary cancer cells revealed by machine learning

Epigenetic Mechanisms in Canine Cancer

Oncolytic effect of Newcastle disease virus is attributed to interferon regulation in canine mammary cancer cell lines

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