scholarly journals ECOA-3. MLL4, UTX, and EZH2 regulate the expression of transcription factors associated with the epithelial-to-mesenchymal transition of lung cancer during metastasis to the brain at posttranscriptional steps

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
Young Zoon Kim
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Lysine Methylation ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
The Brain

Abstract Purpose The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase. And the verification of the present result was performed by qRT-PCR. Results The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%, p = 0.005), Twist (23.6% vs. 45.9%, p = 0.010) and ZEB1 (15.0% vs. 55.9%, p = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, p = 0.018) and H3K36me3 demethylase (UTX, p = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, p = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (R2 linear = 1.204) and MLL4-Slug (R2 linear = 0.987) was increased in direct proportion, and EZH2-Twist (R2 linear = - 2.723) decreased in reverse proportion. The qRT-PCR showed the same results. Conclusion The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain.

scholarly journals Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3632
Author(s):  
Young Min Lee ◽  
Seok Hyun Kim ◽  
Minseok S. Kim ◽  
Dae Cheol Kim ◽  
Eun Hee Lee ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Lysine Methylation ◽  
Mesenchymal Transition ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
The Brain

Purpose: The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods: Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase. Results: The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%, p = 0.005), Twist (23.6% vs. 45.9%, p = 0.010) and ZEB1 (15.0% vs. 55.9%, p = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, p = 0.018) and H3K36me3 demethylase (UTX, p = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, p = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (R2 linear = 1.204) and MLL4-Slug (R2 linear = 0.987) was increased in direct proportion, and EZH2-Twist (R2 linear = −2.723) decreased in reverse proportion. Conclusions: The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain.

scholarly journals SETDB-1: A Potential Epigenetic Regulator in Breast Cancer Metastasis

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1143 ◽  
Author(s):  
Batham ◽  
Lim ◽  
Rao
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Set Domain ◽  
Mesenchymal Transition ◽  
Histone Lysine Methyltransferase ◽  
Epigenetic Regulator ◽  
Lysine Methyltransferase ◽  
Target Cancer

The full epigenetic repertoire governing breast cancer metastasis is not completely understood. Here, we discuss the histone methyltransferase SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1) and its role in breast cancer metastasis. SETDB1 serves as an exemplar of the difficulties faced when developing therapies that not only specifically target cancer cells but also the more elusive and aggressive stem cells that contribute to metastasis via epithelial-to-mesenchymal transition and confer resistance to therapies.

scholarly journals Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Liping Dou ◽  
Fei Yan ◽  
Jiuxia Pang ◽  
Dehua Zheng ◽  
Dandan Li ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Transcriptional Repression ◽  
Lysine Methylation ◽  
Post Translational Modification ◽  
Histone Lysine Methylation ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

Abstract The oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia.

scholarly journals Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

2020 ◽  
Author(s):  
Alexandra L. Berr ◽  
Kristin Wiese ◽  
Gimena dos Santos ◽  
Jennifer M. Davis ◽  
Clarissa M. Koch ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Mouse Model ◽  
Lung Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Differential Expression Analysis ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Lung Cancer Metastasis

AbstractVimentin, a type III intermediate filament, is highly expressed in aggressive epithelial cancers and is associated with increased rates of metastasis. We show that vimentin is causally required for lung cancer metastasis using a genetic mouse model of lung adenocarcinoma (LSL-KrasG12D;Tp53fl/fl, termed KPV+/+) crossed with vimentin-null mice (thereby creating KPV−/− mice). Both KPV+/+ and KPV−/− mice developed lung tumors, yet KPV−/− mice had delayed tumorigenesis and prolonged survival. KPV+/+ cells implanted in the flank metastasized to the lung while KPV−/− cells did not, providing additional evidence that vimentin is required for metastasis. Differential expression analysis of RNA-seq data demonstrated that KPV−/− cells had suppressed expression of genes that drive epithelial-to-mesenchymal transition, migration, and invasion, processes that are critical to the metastatic cascade. Integrative metabolomic and transcriptomic analysis revealed altered glutaminolysis, with KPV−/− cells accumulating glutathione, leading to impaired cell motility in response to oxidative stress. Together, these results show that loss of vimentin impairs epithelial-to-mesenchymal transition and regulation of the oxidative stress response, resulting in decreased metastasis in murine lung adenocarcinoma.

scholarly journals BSCI-16. Olfactory receptor 5B21 drives breast cancer metastasis

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii4-iii4
Author(s):  
Mao Li ◽  
Markus Schweiger ◽  
Ichiro Nakano ◽  
Daniel Ryan ◽  
Litia Carvalho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Olfactory Receptors ◽  
Transcript Abundance ◽  
Breast Cancer Metastasis ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
The Brain

Abstract Olfactory receptors (ORs), responsible for the sense of smell, play an essential role in physiological processes (even outside the nasal epithelium) and cancer. In breast cancer, however, the expression and role of ORs remain understudied. We examined the significance of ORs transcript abundance in breast cancer metastasis to different tissues including the brain, bone, and lung. While we found 20 OR genes to be differentially expressed in different metastasis versus primary tumor, OR5B21 displayed high relation with all metastases. Knockdown of OR5B21 significantly decreased the invasion and migration of breast cancer cells in culture as well as metastasis to different organs including the brain, in vivo. On the other hand, overexpression of OR5B21 in the primary cells had the opposite effect. Mechanistically, OR5B21 was associated with epithelial to mesenchymal transition through STAT3/NFkB/CEBPβ signaling pathway. We propose OR5B21 (and potentially other ORs) as a novel oncogene contributing to breast cancer metastasis, and as a potential target for therapy.

scholarly journals Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 638
Author(s):  
Kittipong Sanookpan ◽  
Nongyao Nonpanya ◽  
Boonchoo Sritularak ◽  
Pithi Chanvorachote
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Colony Formation ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

2021 ◽  
pp. 1-15
Author(s):  
Ping Xu ◽  
Xiao Mo ◽  
Ruixue Xia ◽  
Long Jiang ◽  
Chengfei Zhang ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Lung Adenocarcinoma ◽  
Potassium Channel ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Biology ◽  
Erk Signaling ◽  
Mesenchymal Transition

BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

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