scholarly journals The PRMT7-dependent methylation of shank2 modulates invasion-proliferation switching during breast cancer metastasis

2019 ◽  
Author(s):  
Yingqi Liu ◽  
Xiaoqing Liu ◽  
Lingxia Liu ◽  
Yibo Wang ◽  
Lu Peng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Treatment Strategies ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Proliferation Inhibition ◽  
Arginine Methyltransferase ◽  
Tumour Metastasis

AbstractInvasiveness of cancer cells is associated with proliferation inhibition in multiple types of cancers. Here, we identified the pivotal roles of Arginine methyltransferase PRMT7 in promoting invasion and attenuating proliferation of breast cancer cells. PRMT7 exerted its functions through binding to the scaffold protein shank2 to induce the di-methylation of shank2 at R240. Shank2 R240 methylation exposed ANK domain by disrupting its SPN-ANK domain blockade. Moreover, shank2 R240 methylation rendered recruitment of FAK that elicited the FAK auto-phosphorylation, which consequently augmented the shank2-dependent migration and invasion of breast cancer cells. On the other hand, the shank2 R240 methylation impeded proliferation of breast cancer cells by antagonizing the Ras-Raf binding via tethering the mono-ubiquitinated H-Ras. These findings characterize the PRMT7-dependent shank2 methylation as a key player in mediating reciprocal switching between invasion and proliferation, also point to the value of shank2 R240 methylation as a target for tumour metastasis treatment strategies.

scholarly journals NUPR1 Promotes the Proliferation and Migration of Breast Cancer Cells by Activating TFE3 Transcription to Induce Autophagy

2021 ◽  
Author(s):  
Heng Xiao ◽  
Jing Long ◽  
Xiang Chen ◽  
Mi-Duo Tan
Keyword(s):  
Breast Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Translocation Factor ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Related Proteins

Abstract Background: Breast cancer is a commonplace carcinoma in females. Recurrence and metastasis are the main problems affecting the survival rate of patients. The fundamental reason is the lack of understanding of the mechanism of breast cancer metastasis. This study aims to deliberate on the efficaciousness of Nuclear protein 1 (NUPR1)-mediated autophagy on breast cancer metastasis.Methods: The proliferation, migration and invasion ability of breast cancer cells were appraised by CCK-8, wound healing, and colony formation, as well as transwell assay. The relationship between NUPR1 and Translocation factor E3 (TFE3) was appraised by qPCR, western blot and ChIP. Migration-invasion-related proteins and autophagy-related proteins were appraised by western blot. The effects of NUPR1 on malignancy formation and metastasis were studied in vivo.Results: NUPR1 was upregulated in breast cancer cells and tissues. NUPR1 knockdown restrained the proliferation, migration and invasion of ZR-75-30 cells. Moreover, NUPR1 knockdown restrained malignancy formation and metastasis in vivo. Mechanically, NUPR1 promoted autophagy through activation of TFE3 transcription, thereby regulating the process of breast cancer metastasis.Conclusion: This paper elucidates the molecular mechanism of NUPR1 promoting breast cancer metastasis by activating autophagy through TFE3 signaling pathway, which provided biological basis for intervention of blocking distant metastasis.

Structural Maintenance of Chromosomes 1A (SMC1A) regulated by KIAA1429 in m6A-independent manner promotes EMT progress in breast cancer

2021 ◽  
Author(s):  
Xu Zhang ◽  
Xin-Yuan Dai ◽  
Jia-Yi Qian ◽  
Feng Xu ◽  
Zhang-Wei Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Western Blots ◽  
Potential Biomarker

Abstract Background As a component in the m6A ‘writers’, KIAA1429 was reported to promote breast cancer proliferation and growth in m6A-independent manners. However, the related mechanism of KIAA1429 in breast cancer metastasis have not been reported. Methods Western blots and quantitative real-time PCR were carried out to verify the expression of KIAA1429 in breast cancer cells SUM1315 and ZR-75-1 after KIAA1429 knockdown or overexpression. Transwell and in vivo metastasis assay were conducted to investigate the effects of KIAA1429 on migration and invasion of breast cancer cells. RIP and REMSA assay was performed to explore the direct correlation between KIAA1429 and SMC1A mRNA. ChIP assay combined with luciferase reporter assay were apply to explore the direct binding between SMC1A and SNAIL promotor region. Results KIAA1429 could significantly promote the migration and invasion of breast cancer cells. Knockdown of KIAA1429 could impede breast cancer metastasis in nude mice in vivo. The level of SNAIL expression and EMT progress was positively related with KIAA1429. Knockdown of KIAA1429 induced cell migration, invasion and EMT progress could be reversed by the upregulation of SNAIL. However, SMC1A, not KIAA1429 bound with SNAIL promoter region directly and promoted the transcription of SNAIL. Then, KIAA1429 could bind to the motif in the 3′-UTR of SMC1A mRNA directly and enhanced SMC1A mRNA stability. Conclusions In conclusion, our study revealed a novel mechanism of the KIAA1429/SMC1A/SNAIL axis in the regulation of invasion and metastasis of breast cancer, which may provide a potential biomarker and therapeutic target for breast cancer. Moreover, it firstly provided compelling evidences that KIAA1429 could regulate the targeted gene expression at posttranscriptional levels as an RNA-binding protein, unrelated the m6A modification.

scholarly journals A novel long non-coding RNA AC073352.1 promotes metastasis and angiogenesis via interacting with YBX1 in breast cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xue Kong ◽  
Juan Li ◽  
Yanru Li ◽  
Weili Duan ◽  
Qiuchen Qi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Breast Cancer Patients

AbstractBreast cancer is the major cause of cancer death worldwide in women. Patients with metastasis have poor prognosis and the mechanisms of breast cancer metastasis are not completely understood. Long non-coding RNAs (lncRNAs) have been shown to have crucial roles in breast cancer development and progression. However, the underlying mechanisms by which lncRNA-driven breast cancer metastasis are unknown. The main objective of this paper is to explore a functional lncRNA and its mechanisms in breast cancer. Here we identified a novel lncRNA AC073352.1 that was significantly upregulated in breast cancer tissues and was associated with advanced TNM stages and poor prognosis in breast cancer patients. In addition, AC073352.1 was found to promote the migration and invasion of breast cancer cells in vitro and enhance breast cancer metastasis in vivo. Mechanistically, we elucidated that AC073352.1 interacted with YBX1 and stabilized its protein expression. Knock down of YBX1 reduced breast cancer cell migration and invasion and could partially reverse the stimulative effects of AC073352.1 overexpressed on breast cancer metastasis. Moreover, AC073352.1 might be packaged into exosomes by binding to YBX1 in breast cancer cells resulting in angiogenesis. Collectively, our results demonstrated that AC073352.1 promoted breast cancer metastasis and angiogenesis via binding YBX1, and it could serve as a promising, novel biomarker for prognosis and a therapeutic target in breast cancer.

scholarly journals Biomechanical regulation of breast cancer metastasis and progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adrianne Spencer ◽  
Andrew D. Sligar ◽  
Daniel Chavarria ◽  
Jason Lee ◽  
Darshil Choksi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Mechanical Load ◽  
Breast Cancer Metastasis ◽  
Proliferation And Metastasis ◽  
Xenograft Models ◽  
Chemotherapeutic Treatment ◽  
Complex Signaling

AbstractPhysical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.

scholarly journals Mitochondrial Malic Enzyme 2 Promotes Breast Cancer Metastasis via Stabilizing HIF-1α Under Hypoxia

2021 ◽  
Author(s):  
Duo You ◽  
Danfeng Du ◽  
Xueke Zhao ◽  
Xinmin Li ◽  
Minfeng Ying ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
High Expression ◽  
Breast Cancer Patients ◽  
Cancer Model ◽  
Breast Cancer Model

Abstract Background: α-ketoglutarate (α-KG) is the substrate to hydoxylate collagen and hypoxia-inducible factor-1α (HIF-1α), which are important for cancer metastasis. Previous studies showed that upregulation of collagen prolyl 4-hydroxylase in breast cancer cells stabilizes HIF-1α via depleting α-KG in breast cancer cells. We propose that mitochondrial malate enzyme 2 (ME2) may also affect HIF-1α via modulating α-KG level in breast cancer cells. Methods: ME2 protein expression was evaluated by immunohistochemistry on 100 breast cancer patients and correlated with clinicopathological indicators. The effect of ME2 knockout on cancer metastasis was evaluated by an orthotopic breast cancer model. The effect of ME2 knockout or knockdown on the levels of α-KG and HIF-1α protein in breast cancer cell lines (4T1 and MDA-MB-231) was determined in vitro and in vivo.Results: The high expression of ME2 was observed in the human breast cancerous tissues compared to the matched precancerous tissues (P=0.000). The breast cancer patients with a high expression of ME2 had an inferior survival than the patients with low expression of ME2 (P=0.019). ME2 high expression in breast cancer tissues was also related with lymph node metastasis (P=0.016), pathological staging (P=0.033) and vascular cancer embolus (P=0.014). In a 4T1 orthotopic breast cancer model, ME2 knockout significantly inhibited lung metastasis. In the tumors formed by ME2 knockout 4T1 cells, α-KG level significantly increased, collagen hydroxylation level did not change significantly, but HIF-1α protein level significantly decreased, in comparison to control. In cell culture, ME2 knockout or knockdown cells demonstrated a significantly higher α-KG level but significantly lower HIF-1α protein level than control cells under hypoxia. Exogenous malate and α-KG exerted similar effect on HIF-1α in breast cancer cells to ME2 knockout or knockdown. Treatment with malate significantly decreased 4T1 breast cancer lung metastasis. ME2 expression was associated with HIF-1α level in human breast cancer samples (P=0.027).Conclusion: We provide evidence that upregulation of ME2 is associated with a poor prognosis of breast cancer patients and propose a mechanistic understanding of a link between ME2 and breast cancer metastasis.

BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13002-e13002
Author(s):  
Yinghuan Cen ◽  
Chang Gong ◽  
Jun Li ◽  
Gehao Liang ◽  
Zihao Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Qrt Pcr ◽  
Metastatic Sites

e13002 Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.

miR-214 inhibits epithelial–mesenchymal transition of breast cancer cells via downregulation of RNF8

2019 ◽  
Vol 51 (8) ◽  
pp. 791-798 ◽  
Author(s):  
Lu Min ◽  
Chuanyang Liu ◽  
Jingyu Kuang ◽  
Xiaomin Wu ◽  
Lingyun Zhu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Proliferation And Invasion

Abstract MicroRNAs (miRNAs) are a class of endogenous noncoding genes that regulate gene expression at the posttranscriptional level. In recent decades, miRNAs have been reported to play important roles in tumor growth and metastasis, while some reported functions of a specific miRNA in tumorigenesis are contradictory. In this study, we reevaluated the role of miR-214, which has been reported to serve as an oncogene or anti-oncogene in breast cancer metastasis. We found that miR-214 inhibited breast cancer via targeting RNF8, a newly identified regulator that could promote epithelial–mesenchymal transition (EMT). Specifically, the survival rate of breast cancer patients was positively correlated with miR-214 levels and negatively correlated with RNF8 expression. The overexpression of miR-214 inhibited cell proliferation and invasion of breast cancer, while suppression of miR-214 by chemically modified antagomir enhanced the proliferation and invasion of breast cancer cells. Furthermore, miR-214 could modulate the EMT process via downregulating RNF8. To our knowledge, this is the first report that reveals the role of the miR-214–RNF8 axis in EMT, and our results demonstrate a novel mechanism for miR-214 acting as a tumor suppressor through the regulation of EMT.

scholarly journals The long non-coding RNA ET-20 mediates EMT by impairing desmosomes in breast cancer cells

2021 ◽  
Author(s):  
Meera Saxena ◽  
Mizue Hisano ◽  
Melanie Neutzner ◽  
Maren Diepenbruck ◽  
Robert Ivanek ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Matrix Protein ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Invasive Human Breast Cancer

The vast majority of breast cancer-associated deaths are due to metastatic spread of cancer cells, a process aided by epithelial-mesenchymal transition (EMT). Mounting evidence has indicated that long non-coding RNAs (lncRNAs) also contribute to tumor progression. We report the identification of 114 novel lncRNAs that change their expression during TGFβ-induced EMT in murine breast cancer cells (referred to as EMT-associated transcripts; ETs). Of these, the ET-20 gene localizes in antisense orientation within the Tenascin C (Tnc) gene locus. Tnc is an extra-cellular matrix protein which is critical for EMT and metastasis formation. Both ET-20 and Tnc are regulated by the EMT master transcription factor Sox4. Notably, ablation of ET-20 lncRNA effectively blocks Tnc expression and with it EMT. Mechanistically, ET-20 interacts with desmosomal proteins, thereby impairing epithelial desmosomes and promoting EMT. A short transcript variant of ET-20 is found upregulated in invasive human breast cancer cell lines where it also promotes EMT. Targeting ET-20 appears a therapeutically attractive lead to restrain EMT and breast cancer metastasis in addition to its potential utility as a biomarker for invasive breast cancer.

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.

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