scholarly journals Inhibition of the histone demethylase, KDM5B, directly induces re-expression of tumor suppressor protein HEXIM1 in cancer cells

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Monica M. Montano ◽  
I-Ju Yeh ◽  
Yinghua Chen ◽  
Chris Hernandez ◽  
Janna G. Kiselar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Cell Phenotype ◽  
Relative Role ◽  
Western Blots ◽  
Inhibition Of Proliferation ◽  
Proliferation Assays

Abstract Background The tumor suppressor actions of hexamethylene bis-acetamide (HMBA)-inducible protein 1 (HEXIM1) in the breast, prostate, melanomas, and AML have been reported by our group and others. Increased HEXIM1 expression caused differentiation and inhibited proliferation and metastasis of cancer cells. Historically, HEXIM1 has been experimentally induced with the hybrid polar compound HMBA, but HMBA is a poor clinical candidate due to lack of a known target, poor pharmacological properties, and unfavorable ADMETox characteristics. Thus, HEXIM1 induction is an intriguing therapeutic approach to cancer treatment, but requires better chemical tools than HMBA. Methods We identified and verified KDM5B as a target of HEXIM1 inducers using a chemical proteomics approach, biotin–NeutrAvidin pull-down assays, surface plasmon resonance, and molecular docking. The regulation of HEXIM1 by KDM5B and KDM5B inhibitors was assessed using chromatin immunoprecipitation assays, RT-PCR, western blotting, and depletion of KDM5B with shRNAs. The regulation of breast cancer cell phenotype by KDM5B inhibitors was assessed using western blots, differentiation assays, proliferation assays, and a mouse model of breast cancer metastasis. The relative role of HEXIM1 in the action of KDM5B inhibitors was determined by depleting HEXIM1 using shRNAs followed by western blots, differentiation assays, and proliferation assays. Results We have identified a highly druggable target, KDM5B, which is inhibited by small molecule inducers of HEXIM1. RNAi knockdown of KDM5B induced HEXIM1 expression, thus validating the specific negative regulation of tumor suppressor HEXIM1 by the H3K4me3/2 demethylase KDM5B. Known inhibitors of KDM5B were also able to induce HEXIM1 expression, inhibit cell proliferation, induce differentiation, potentiate sensitivity to cancer chemotherapy, and inhibit breast tumor metastasis. Conclusion HMBA and 4a1 induce HEXIM1 expression by inhibiting KDM5B. Upregulation of HEXIM1 expression levels plays a critical role in the inhibition of proliferation of breast cancer cells using KDM5B inhibitors. Based on the novel molecular scaffolds that we identified which more potently induced HEXIM1 expression and data in support that KDM5B is a target of these compounds, we have opened up new lead discovery and optimization directions.

scholarly journals S100A4 released from highly bone-metastatic breast cancer cells plays a critical role in osteolysis

Bone Research ◽  
2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Haemin Kim ◽  
Bongjun Kim ◽  
Sang Il Kim ◽  
Hyung Joon Kim ◽  
Brian Y. Ryu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Bone Loss ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Bone Destruction ◽  
Metastatic Breast ◽  
Breast Cancer Patients

Abstract Bone destruction induced by breast cancer metastasis causes severe complications, including death, in breast cancer patients. Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis. Tumor-derived factors play fundamental roles in this form of communication. To identify soluble factors released from cancer cells in bone metastasis, we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells. This subline (mtMDA) showed a markedly elevated ability to secrete S100A4 protein, which directly stimulated osteoclast formation via surface receptor RAGE. Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo. Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts. Furthermore, the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells. In addition, administration of an anti-S100A4 monoclonal antibody (mAb) that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice. Taken together, our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.

scholarly journals lncRNA APOC1P1-3 promoting anoikis-resistance of breast cancer cells

2020 ◽  
Author(s):  
Qi Lu ◽  
Li Wang ◽  
Ping Zhu ◽  
Luying Li ◽  
Xue Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Breast Cancer Cell Lines ◽  
Anoikis Resistance ◽  
Apoptosis Protein

Abstract Background Anoikis resistance plays a critical role in the tumor metastasis by allowing survival of cancer cells in the systemic circulation. We previously showed that long non-coding RNAs APOC1P1-3 (lncRNA APOC1P1-3) inhibits breast cancer cell apoptosis. However, its role in the anoikis resistance remains unclear. Methods We induced anoikis resistance in two breast cancer cell lines (MCF-7 and MDA-MB-231) under anchorage-independent culture condition and studied the effects of lncRNA APOC1P1-3 on the apoptosis. The Dual-Luciferase activity assay were used to whether miRNA-188-3P can specifically bind to lncRNA APOC1P1-3. We further explored the role of APOC1P1-3 in the lung metastasis by injecting MDA-MB-231 and MDA-MB-231-APOC1P1-3-knock-down cells in the female BALB/c nude mice. Results We found that it suppressed early apoptosis of these cells by gain or loss of their function, respectively. We further explored its mechanism related to anoikis resistance, and found this molecule promoted the resistance via activating Caspase 3, 8, 9 and PARP. Moreover, it was specifically binding to the target miRNA-188-3p to block its inhibition of Bcl-2 (an anti-apoptosis protein). These findings suggest that lncRNA APOC1P1-3 plays an important role in the development of breast cancer metastasis via anoikis resistance. Conclusions This study demonstrates that lncRNA APOC1P1-3 can promote the anoikis resistance of breast cancer cells and specifically bind to miRNA-188-3p acting as a “sponge” to block the inhibition of anti-apoptotic protein Bcl-2.

scholarly journals lncRNA APOC1P1-3 promoting anoikis-resistance of breast cancer cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qi Lu ◽  
Li Wang ◽  
Yabiao Gao ◽  
Ping Zhu ◽  
Luying Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Systemic Circulation ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Anoikis Resistance ◽  
Apoptosis Protein

Abstract Background Anoikis resistance plays a critical role in the tumor metastasis by allowing survival of cancer cells in the systemic circulation. We previously showed that long non-coding RNAs APOC1P1-3 (lncRNA APOC1P1-3) inhibit apoptosis of breast cancer cells. In this study, we explored its role in anoikis resistance. Methods We induced anoikis resistance in two breast cancer cell lines (MCF-7 and MDA-MB-231) under anchorage-independent culture conditions and studied lncRNA APOC1P1-3 effects on apoptosis. Using Dual-Luciferase activity assay, we determined whether it specifically binds to miRNA-188-3P. We further explored its role in lung metastasis by injecting MDA-MB-231 and MDA-MB-231-APOC1P1-3-knock-down cells in female BALB/c nude mice. Results We found that lncRNA APOC1P1-3 suppressed early apoptosis of these cells (demonstrated by gain or loss of their function, respectively) and promoted anoikis resistance via reducing activated- Caspase 3, 8, 9 and PARP. Moreover, it specifically binds to the target miRNA-188-3p acting as a “sponge” to block the inhibition of Bcl-2 (an anti-apoptosis protein). Conclusions Our study supports a theory that lncRNA APOC1P1-3 can promote development of breast cancer metastasis via anoikis resistance by specifically binding to miRNA-188-3p to block the inhibition of Bcl-2.

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 MicroRNA-200c Overexpression in Cancer-Associated Fibroblasts Reduces the Invasive Properties of Breast Cancer Cells: An Approach to Molecular Therapy

2021 ◽  
Author(s):  
Nasim Shenavar ◽  
Laleh Shariati ◽  
Mohammad Reza Hakimian ◽  
Shaghayegh Haghjooy Javanmard
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Critical Role ◽  
Molecular Therapy ◽  
Cancer Development ◽  
Cancer Associated Fibroblasts ◽  
Cancer Breast ◽  
Aggressive Subtype ◽  
Common Malignancy

Abstract BackgroundThe most common malignancy is breast cancer, among women in the world. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Cancer associated fibroblasts (CAFs) play a critical role to support tumor cells in all aspect of cancer development such as cell proliferation, migration and angiogenesis. MiRNAs are one of the regulatory molecules that regulate the genes contributing to cell growth, differentiation, migration and apoptosis. Based on other studies, miR-200c, as a tumor suppressor, has low expression levels in cancer associated fibroblasts. In this investigation, effect of miR-200c overexpression was evaluated on proliferation, migration and angiogenesis of TNBC cells. MethodsThe fibroblasts were isolated from normal and cancer breast tissue. MiR-200c expression was assessed using RT PCR in cancer associated fibroblasts (CAFs) and normal fibrobalasts (NFs) and then, were transfected using miR-200c. Finally, its effect on proliferation, migration and angiogenesis of TNBC cells were evaluated. ResultsOur results confirm that in presence of miR-200c transfected fibroblasts, the proliferation, migration and angiogenesis of cancer cells significantly decreased. This effect may be due to the reduction of growth factors provided by CAFs after miRNAs dysregulation. ConclusionThese results suggest miR-200c act as an effective tumor suppressor in many aspects of TNBC cancer development and can be regarded as a potential therapeutic tool for breast cancer in the future.

scholarly journals LncRNA APOC1P1-3 Promoting Anoikis-resistance of Breast Cancer Cells

2020 ◽  
Author(s):  
Qi Lu ◽  
Li Wang ◽  
Ping Zhu ◽  
Yabiao Gao ◽  
Luying Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Breast Cancer Cell Lines ◽  
Anoikis Resistance ◽  
Apoptosis Protein

Abstract Background: Anoikis resistance plays a critical role in the tumor metastasis by allowing survival of cancer cells in the systemic circulation. We previously showed that long non-coding RNAs APOC1P1-3 (lncRNA APOC1P1-3) inhibits breast cancer cell apoptosis. However, its role in the anoikis resistance remains unclear. Methods: We induced anoikis resistance in two breast cancer cell lines (MCF-7 and MDA-MB-231) under anchorage-independent culture condition and studied the effects of lncRNA APOC1P1-3 on the apoptosis. The Dual-Luciferase activity assay were used to whether miRNA-188-3P can specifically bind to lncRNA APOC1P1-3. We further explored the role of APOC1P1-3 in the lung metastasis by injecting MDA-MB-231 and MDA-MB-231-APOC1P1-3-knock-down cells in the female BALB/c nude mice.Results: We found that it suppressed early apoptosis of these cells by gain or loss of their function, respectively. We further explored its mechanism related to anoikis resistance, and found this molecule promoted the resistance via activating Caspase 3, 8, 9 and PARP. Moreover, it was specifically binding to the target miRNA-188-3p to block its inhibition of Bcl-2 (an anti-apoptosis protein). These findings suggest that lncRNA APOC1P1-3 plays an important role in the development of breast cancer metastasis via anoikis resistance. Conclusions: This study demonstrates that lncRNA APOC1P1-3 can promote the anoikis resistance of breast cancer cells and specifically bind to miRNA-188-3p acting as a “sponge” to block the inhibition of anti-apoptotic protein Bcl-2.

scholarly journals LncRNA APOC1P1-3 promoting anoikis-resistance of breast cancer cells

2020 ◽  
Author(s):  
Qi Lu ◽  
Li Wang ◽  
Ping Zhu ◽  
Luying Li ◽  
Xue Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Breast Cancer Cell Lines ◽  
Anoikis Resistance ◽  
Apoptosis Protein

Abstract Background Anoikis resistance plays a critical role in the tumor metastasis by allowing survival of cancer cells in the systemic circulation. We previously showed that long non-coding RNAs APOC1P1-3 (lncRNA APOC1P1-3) inhibits breast cancer cell apoptosis. However, its role in the anoikis resistance remains unclear. Methods We induced anoikis resistance in two breast cancer cell lines (MCF-7 and MDA-MB-231) under anchorage-independent culture condition and studied the effects of lncRNA APOC1P1-3 on the apoptosis. The Dual-Luciferase activity assay were used to whether miRNA-188-3P can specifically bind to lncRNA APOC1P1-3. We further explored the role of APOC1P1-3 in the lung metastasis by injecting MDA-MB-231 and MDA-MB-231-APOC1P1-3-knock-down cells in the female BALB/c nude mice. Results We found that it suppressed early apoptosis of these cells by gain or loss of their function, respectively. We further explored its mechanism related to anoikis resistance, and found this molecule promoted the resistance via activating Caspase 3, 8, 9 and PARP. Moreover, it was specifically binding to the target miRNA-188-3p to block its inhibition of Bcl-2 (an anti-apoptosis protein). These findings suggest that lncRNA APOC1P1-3 plays an important role in the development of breast cancer metastasis via anoikis resistance. Conclusions This study demonstrates that lncRNA APOC1P1-3 can promote the anoikis resistance of breast cancer cells and specifically bind to miRNA-188-3p acting as a “sponge” to block the inhibition of anti-apoptotic protein Bcl-2.

scholarly journals The downregulation of WWOX induces epithelial–mesenchymal transition and enhances stemness and chemoresistance in breast cancer

2018 ◽  
Vol 243 (13) ◽  
pp. 1066-1073 ◽  
Author(s):  
Juan Li ◽  
Jie Liu ◽  
Pingping Li ◽  
Can Zhou ◽  
Peijun Liu
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Tumor Suppressor ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cell Phenotype ◽  
Ww Domain ◽  
Mesenchymal Transition

WW domain-containing oxidoreductase (WWOX), an important tumor suppressor, is essential for regulating cell proliferation and apoptosis. Our study demonstrates that low level of WWOX is associated with the triple-negative subtype of breast cancer (TNBC), which has higher stem cell phenotype and chemoresistance. We evaluated the role of WWOX in regulation of breast cancer stem cells (BCSC) phenotype and chemoresistance. Our results showed that knockdown of WWOX increases the stemness of breast cancer cells. Meanwhile, downregulation of WWOX induces the epithelial–mesenchymal transition (EMT) and chemoresistance of breast cancer cell lines. Our findings revealed the role of the WWOX in the regulation of the BCSC population and chemotherapeutic sensitivity and may provide insights for the development of more effective therapies targeting cancer stem cells in breast cancer. Impact statement Overcoming resistance to chemotherapy is one of the fundamental issues of clinical treatment and CSCs are responsible for the poor therapeutic effects of chemotherapy. WW domain-containing oxidoreductase (WWOX), an important tumor suppressor, regulates cancer cells’ response to chemotherapy. The major finding of our study is the novel role of WWOX in the chemoresistance of breast cancer through the regulation of cell stemness and EMT. The plasticity may play a crucial role in tumor metastasis, treatment resistance and tumor recurrence. Our findings may shed new light on the alterations of BCSCs and pave the way for the discovery of novel and more effective therapies to treat breast cancer by targeting WWOX.

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