scholarly journals Epigenetic Regulation of CDH1 Is Altered after HOXB7-Silencing in MDA-MB-468 Triple-Negative Breast Cancer Cells

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1575
Author(s):  
Ana Paço ◽  
Joana Leitão-Castro ◽  
Renata Freitas
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Epigenetic Regulation ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Methylation Status ◽  
Therapy Resistance ◽  
Migration And Invasion ◽  
A Cells

HOXB7 is often overexpressed in breast cancer cells and found to relate to poor prognosis. The search for the HOXB7 targets, as a transcription factor, has led to molecules involved in regulating cell proliferation, migration, invasion, and processes such as angiogenesis and therapy resistance. However, the specific targets affected by the deregulation of HOXB7 in breast cancer remain largely unknown in most molecular sub-types, such as triple-negative breast cancers (TNBC). To unveil the molecular basis behind these aggressive and often untreatable cancers, here we explored the contribution of HOXB7 deregulation for their aggressiveness. To this end, HOXB7 was silenced in TNBC Basal A cells MDA-MB-468, and the phenotype, gene/protein expression, and methylation profile of putative targets were analyzed. Lower migration and invasion rates were detected in HOXB7-silenced cells in comparison with the controls. In addition, these cells expressed more CDH1 and less DNMT3B, and the promoter methylation status of CDH1 diminished. Our data suggest that the HOXB7 transcription factor may act on TNBC Basal A cells by controlling CDH1 epigenetic regulation. This may occur indirectly through the up-regulation of DNMT3B, which then controls DNA methylation of the CDH1 promoter. Thus, future approaches interfering with HOXB7 regulation may be promising therapeutic strategies in TNBC treatment.

scholarly journals The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Ziyu Zhang ◽  
Baoyu Chen ◽  
Yuwen Zhu ◽  
Tianyi Zhang ◽  
Yibiao Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Rna Polymerase Ii ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Methylation Status ◽  
Small Gtpase ◽  
Epigenetic Mechanism ◽  
Migration And Invasion ◽  
Breast Cancer Patients

The small GTPase RHOJ is a key regulator of breast cancer metastasis by promoting cell migration and invasion. The prometastatic stimulus TGF-β activates RHOJ transcription via megakaryocytic leukemia 1 (MKL1). The underlying epigenetic mechanism is not clear. Here, we report that MKL1 deficiency led to disrupted assembly of the RNA polymerase II preinitiation complex on the RHOJ promoter in breast cancer cells. This could be partially explained by histone H3K9/H3K27 methylation status. Further analysis confirmed that the H3K9/H3K27 dual demethylase JHDM1D/KDM7A was essential for TGF-β-induced RHOJ transcription in breast cancer cells. MKL1 interacted with and recruited KDM7A to the RHOJ promoter to cooperatively activate RHOJ transcription. KDM7A knockdown attenuated migration and invasion of breast cancer cells in vitro and mitigated the growth and metastasis of breast cancer cells in nude mice. KDM7A expression level, either singularly or in combination with that of RHOJ, could be used to predict prognosis in breast cancer patients. Of interest, KDM7A appeared to be a direct transcriptional target of TGF-β signaling. A SMAD2/SMAD4 complex bound to the KDM7A promoter and mediated TGF-β-induced KDM7A transcription. In conclusion, our data unveil a novel epigenetic mechanism whereby TGF-β regulates the transcription of the prometastatic small GTPase RHOJ. Screening for small-molecule inhibitors of KDM7A may yield effective therapeutic solutions to treat malignant breast cancers.

scholarly journals Shikonin inhibits migration and invasion of triple-negative breast cancer cells by suppressing epithelial-mesenchymal transition via miR-17-5p/PTEN/Akt pathway

2020 ◽  
Author(s):  
Chang Bao ◽  
Tao Liu ◽  
Lingbo Qian ◽  
Chi Xiao ◽  
Xinru Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Pathway Enrichment Analysis ◽  
Mesenchymal Transition

Abstract Background: Triple-negative breast cancer(TNBC) is a great threat to global women’s health due to its high metastatic potential. Epithelial-to-mesenchymal transition (EMT) is considered as a key event in the process of metastasis. So the pharmacological targeting of EMT might be a promising strategy in improving the therapeutic efficacy of TNBC. Here, we investigated the effect of shikonin exerting on EMT and consequently the metastasis of TNBC cells and its underlying mechanism.Methods: The invasive and migratory capacities of MDA-MB-231 cells were tested using transwell invasion and wound healing assay. MiR-17-5p expression was examined by qRT-PCR. MiR-17-5p targeted genes were predicted with different bioinformatic algorithms from four databases (TargetScan, miRanda, PITA and picTar) and further screened by KEGG pathway enrichment analysis. The differential expressions of predicted genes and their correlations with miR-17-5p were identifed in breast cancer patients based on The Cancer Genome Atlas (TCGA) database. The interaction between PTEN and miR-17-5p was analyzed by luciferase reporter assay. The overexpression vector and small interfering RNA were constructed to investigate the role PTEN played in matastasis and EMT regulation. The expressions of EMT markers, Akt and p-Akt were evaluated by western blot.Results: Shikonin inhibited the migration and invasion of MDA-MB-231 cells by suppressing EMT. Shikonin suppressed the expression of miR-17-5p, which was upregulated in breast cancer and promoted cancer cell migration, invasion and EMT. The 3’-untranslated region of PTEN was found to be direct binding target of miR-17-5p. PTEN expression increased or decreased in breast cancer cells transfected with miR-17-5p inhibitors or mimics respectively. PTEN functioned as a suppressor both in the metastasis and EMT of TNBC cells. Overexpression or knockdown of PTEN reduced or increased the Akt and p-Akt expression respectively.Conclusions: Shikonin inhibits migration and invasion of TNBC cells by suppressing EMT via miR-17-5p/PTEN/Akt pathway. This suggests shikonin as a promising therapeutic agent to counteract metastasis in the TNBC patients.

scholarly journals FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells

Oncotarget ◽  
2015 ◽  
Vol 6 (7) ◽  
pp. 4757-4772 ◽  
Author(s):  
LaTonia Taliaferro-Smith ◽  
Elaine Oberlick ◽  
Tongrui Liu ◽  
Tanisha McGlothen ◽  
Tiffanie Alcaide ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Migration And Invasion

scholarly journals Knockdown of A-kinase anchor protein 4 inhibits proliferation of triple-negative breast cancer cells in vitro and in vivo

Tumor Biology ◽  
2020 ◽  
Vol 42 (4) ◽  
pp. 101042832091447 ◽  
Author(s):  
Nirmala Jagadish ◽  
Sonika Devi ◽  
Namita Gupta ◽  
Vitusha Suri ◽  
Anil Suri
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Cytotoxic Effect ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Anchor Protein

Triple-negative breast cancers are the most aggressive subtypes with poor prognosis due to lack of targeted cancer therapy. Recently, we reported an association of A-kinase anchor protein 4 expression with various clinico-pathological parameters of breast cancer patients. In this context, we examined the effect of knockdown of A-kinase anchor protein 4 on cell cycle, apoptosis, cellular proliferation, colony formation, migration, and invasion in triple-negative breast cancer cells. We also examined the synergistic cytotoxic effect of paclitaxel on A-kinase anchor protein 4 downregulated triple-negative breast cancer cells. Knockdown of A-kinase anchor protein 4 resulted in significant reduction in cellular growth and migratory abilities. Interestingly, we also observed enhanced cell death in A-kinase anchor protein 4 downregulated cells treated with paclitaxel. Knockdown of A-kinase anchor protein 4 in cell cycle resulted in G0/G1 phase arrest. Knockdown of A-kinase anchor protein 4 also led to increased reactive oxygen species generation as a result of upregulation of NOXA and CHOP. In addition, levels of cyclins, cyclin-dependent kinases, anti-apoptotic molecules, and mesenchymal markers were reduced in A-kinase anchor protein 4 downregulated cells. Moreover, downregulation of A-kinase anchor protein 4 also caused tumor growth reduction in in vivo studies. These data together suggest that A-kinase anchor protein 4 downregulation inhibits various malignant properties and enhances the cytotoxic effect of paclitaxel, and this combinatorial approach could be useful for triple-negative breast cancer treatment.

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