Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice

Ovarian cancer (OC) is one of the deadliest cancers among women contributing to high risk of mortality, mainly owing to delayed detection. There is no specific biomarker for its detection in early stages. However, recent findings show that over-expression of specificity protein 1 (Sp1) is involved in many OC cases. The ubiquitous transcription of Sp1 apparently mediates the maintenance of normal and cancerous biological processes such as cell growth, differentiation, angiogenesis, apoptosis, cellular reprogramming and tumorigenesis. Sp1 exerts its effects on cellular genes containing putative GC–rich Sp1–binding site in their promoters. A better understanding of the mechanisms underlying Sp1 transcription factor (TF) regulation and functions in OC tumorigenesis could help identify novel prognostic markers, to target cancer stem cells (CSCs) by following cellular reprogramming and enable the development of novel therapies for future generations. In this review, we address the structure, function, and biology of Sp1 in normal and cancer cells, underpinning the involvement of Sp1 in OC tumorigenesis. In addition, we have highlighted the influence of Sp1 TF in cellular reprogramming of iPSCs and how it plays a role in controlling CSCs. This review highlights the drugs targeting Sp1 and their action on cancer cells. In conclusion, we predict that research in this direction will be highly beneficial for OC treatment, and chemotherapeutic drugs targeting Sp1 will emerge as a promising therapy for OC.

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Silencing of Transcription Factor Sp1 Promotes SN1 Transporter Regulation by Ammonia in Mouse Cortical Astrocytes

International Journal of Molecular Sciences ◽

10.3390/ijms20020234 ◽

2019 ◽

Vol 20 (2) ◽

pp. 234 ◽

Cited By ~ 2

Author(s):

Katarzyna Dąbrowska ◽

Magdalena Zielińska

Keyword(s):

Transcription Factor ◽

Cellular Localization ◽

Sp1 Transcription Factor ◽

Kinase C ◽

Cultured Astrocytes ◽

Pkc Isoforms ◽

Specificity Protein ◽

Glutamine Uptake

The involvement of the astrocytic SN1 (SNAT3) transporter in ammonia-induced l-glutamine retention was recently documented in mouse-cultured astrocytes. Here we investigated the involvement of specificity protein 1 (Sp1) transcription factor in SN1 regulation in ammonium chloride (“ammonia”)-treated astrocytes. Sp1 expression and its cellular localization were determined using real-time qPCR, Western blot, and confocal microscopy. Sp1 binding to Snat3 promoter was analyzed by chromatin immunoprecipitation. The role of Sp1 in SN1 expression and SN1-mediated [3H]glutamine uptake in ammonia-treated astrocytes was verified using siRNA and mithramycin A. The involvement of protein kinase C (PKC) isoforms in Sp1 level/phosphorylation status was verified using siRNA technology. Sp1 translocation to the nuclei and its enhanced binding to the Snat3 promoter, along with Sp1 dependence of system N-mediated [3H]glutamine uptake, were observed in astrocytes upon ammonia exposure. Ammonia decreased the level of phosphorylated Sp1, and the effect was reinforced by long-term incubation with PKC modulator, phorbol 12-myristate 13-acetate, which is a treatment likely to dephosphorylate Sp1. Furthermore, silencing of the PKCδ isoform appears to enhance the ammonia effect on the Sp1 level. Collectively, the results demonstrate the regulatory role of Sp1 in regulation of SN1 expression and activity in ammonia-treated astrocytes and implicate altered Sp1 phosphorylation status in this capacity.

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The BRCA2 p.N372 H i.a.1342A>C Could Regulate the Sensitivity of Ovarian Cancer Cells to Platinum-Based Drugs

Technology in Cancer Research & Treatment ◽

10.1177/1533033820983289 ◽

2020 ◽

Vol 19 ◽

pp. 153303382098328

Author(s):

Zhen-Hua Du ◽

Yu Xia ◽

Qing Yang ◽

Song Gao

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Mutant Gene ◽

Negative Control ◽

Ovarian Cancer Cells ◽

Platinum Resistance ◽

Over Expression ◽

Ic50 Value ◽

Brca2 Protein ◽

Recombination Repair

Background and Objective: We have previously reported that BRCA2 N372 H i.a.1342A>C heterozygous variation presented in platinum-resistant patients. This study aimed to further investigate the mechanism of BRCA2 N372 H mutation in the development of platinum resistance in ovarian cancer. Methods: The BRCA2 N372 H i.a.1342A>C was synthesized and used to exchange 1 wildtype allele followed by sequencing to confirm the mutant allele sequence. Plasmids were constructed and transfected into the OVCAR-3 cells after lentiviral packaging. BRCA2 N372 H mRNA was detected by qPCR. BRCA2 protein was assessed by immunoblotting. Binding of the BRCA2 to Rad51 was detected by immunofluorescence staining. Sensitivity of the cells to cisplatin treatment was assessed with CCK-8 assay. Results: It was found that expression of BRCA2 protein in ovarian cancer cells transfected with BRCA2 N372 H i.a.1342A>C gene (2.177 ± 0.003) was significantly increased compared to that of the cells transfected with lenti-EGFP only (1.227 ± 0.003, P < 0.001). Binding of the BRCA2 and Rad51 proteins was significantly increased in the cells with BRCA2 N372 H i.a.1342A>C mutation (3.542 ± 0.24) than that in the cells transfected with lenti-EGFP (1.29 ± 0.32) or empty cells (1.363 ± 0.32, P < 0.001). Cell viability significantly increased in the cells transfected with BRCA2 N372 H mutant gene. The IC50 value was significantly higher in the cells transfected with BRCA2 N372 H mutant gene (1.963 ± 0.04) than that of the cells transfected with lenti-EGFP (0.955 ± 0.03, P < 0.01) or empty cells (1.043 ± 0.007, P < 0.01). Conclusion: Over expression of mRNA and protein of BRCA2 was detected in the cells with BRCA2 N372 H i.a.1342A>C mutation but not in the lentivirus negative control (lenti-EGFP) or the cells without transfection (empty cells), which may lead to resistance to platinum-based drugs in ovarian cancer cells through homologous recombination repair pathway.

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Hsa_circ_0026628 promotes the development of colorectal cancer by targeting SP1 to activate the Wnt/β-catenin pathway

Cell Death and Disease ◽

10.1038/s41419-021-03794-6 ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Xuexiu Zhang ◽

Jianning Yao ◽

Haoling Shi ◽

Bing Gao ◽

Haining Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Transcription Factor ◽

Circular Rna ◽

Luciferase Reporter ◽

Circular Rnas ◽

Transcriptional Level ◽

Sp1 Transcription Factor ◽

Reporter Assays ◽

Sphere Formation

AbstractCircular RNAs (circRNAs) have been reported to play crucial roles in the progression of various cancers, including colorectal cancer (CRC). SP1 (Sp1 transcription factor) is a well-recognized oncogene in CRC and is deemed to trigger the Wnt/β-catenin pathway. The present study was designed to investigate the role of circRNAs which shared the same pre-mRNA with SP1 in CRC cells. We identified that hsa_circ_0026628 (circ_0026628), a circular RNA that originated from SP1 pre-mRNA, was upregulated in CRC cells. Sanger sequencing and agarose gel electrophoresis verified the circular characteristic of circ_0026628. Functional assays including CCK-8, colony formation, transwell, immunofluorescence staining, and sphere formation assay revealed the function of circ_0026628. RNA pull-down and mass spectrometry disclosed the proteins interacting with circ_0026628. Mechanistic assays including RIP, RNA pull-down, CoIP, ChIP, and luciferase reporter assays demonstrated the interplays between molecules. The results depicted that circ_0026628 functioned as a contributor to CRC cell proliferation, migration, EMT, and stemness. Mechanistically, circ_0026628 served as the endogenous sponge of miR-346 and FUS to elevate SP1 expression at the post-transcriptional level, thus strengthening the interaction between SP1 and β-catenin to activate the Wnt/β-catenin pathway. In turn, the downstream gene of Wnt/β-catenin signaling, SOX2 (SRY-box transcription factor 2), transcriptionally activated SP1 and therefore boosted circ_0026628 level. On the whole, SOX2-induced circ_0026628 sponged miR-346 and recruited FUS protein to augment SP1, triggering the downstream Wnt/β-catenin pathway to facilitate CRC progression.

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The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

Tumor Biology ◽

10.1177/1010428317705508 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831770550 ◽

Cited By ~ 4

Author(s):

Yi Li ◽

Ming Xiao ◽

Fangchun Guo

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Conditioned Medium ◽

Umbilical Vein ◽

Inhibitory Effect ◽

Ovarian Cancer Cells ◽

Human Umbilical Vein ◽

Tumor Tissues

SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.

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The role of the globular heads of the C1q receptor in paclitaxel-induced human ovarian cancer cells apoptosis by a mitochondria-dependent pathway

Anti-Cancer Drugs ◽

10.1097/cad.0000000000000567 ◽

2017 ◽

pp. 1 ◽

Cited By ~ 2

Author(s):

Kang-Tai Lv ◽

Ling-Juan Gao ◽

Xiangdong Hua ◽

Fengshan Li ◽

Yun Gu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Dependent Pathway

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Role of Rb Family in Vitamin D Receptor-Mediated Anti-Tumor Effects in Ovarian Cancer Cells.

10.1210/endo-meetings.2010.part1.p1.p1-9 ◽

2010 ◽

pp. P1-9-P1-9

Author(s):

J Tang ◽

P Li ◽

AKW Tse ◽

SV Nicosia ◽

X Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Vitamin D ◽

Cancer Cells ◽

Vitamin D Receptor ◽

Ovarian Cancer Cells

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How cancer cells remodel lipid metabolism: strategies targeting transcription factors

Lipids in Health and Disease ◽

10.1186/s12944-021-01593-8 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Do-Won Jeong ◽

Seulbee Lee ◽

Yang-Sook Chun

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Lipid Metabolism ◽

Cancer Cells ◽

Cancer Biology ◽

Factors Associated ◽

Modeling Techniques ◽

Related Enzyme ◽

Potential Strategy

AbstractReprogramming of lipid metabolism has received increasing recognition as a hallmark of cancer cells because lipid dysregulation and the alteration of related enzyme profiles are closely correlated with oncogenic signals and malignant phenotypes, such as metastasis and therapeutic resistance. In this review, we describe recent findings that support the importance of lipids, as well as the transcription factors involved in cancer lipid metabolism. With recent advances in transcription factor analysis, including computer-modeling techniques, transcription factors are emerging as central players in cancer biology. Considering the limited number and the crucial role of transcription factors associated with lipid rewiring in cancers, transcription factor targeting is a promising potential strategy for cancer therapy.

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Transgelin interacts with PARP1 and affects Rho signaling pathway in human colon cancer cells

10.21203/rs.3.rs-15780/v1 ◽

2020 ◽

Author(s):

Zhen-xian Lew ◽

Hui-min Zhou ◽

Yuan-yuan Fang ◽

Zhen Ye ◽

Wa Zhong ◽

...

Keyword(s):

Mass Spectrometry ◽

Colon Cancer ◽

Transcription Factor ◽

High Performance Liquid Chromatography ◽

Cancer Cells ◽

Signaling Pathway ◽

High Performance ◽

Colon Cancer Cells ◽

Over Expression ◽

Key Genes

Abstract Background: Transgelin, an actin-binding protein, is associated with the cytoskeleton remodeling. Our previous studies found that transgelin was up-regulated in node-positive colorectal cancer versus in node-negative disease. Over-expression of TAGLN affected the expression of 256 downstream transcripts and increased the metastatic potential of colon cancer cells in vitro and in vivo. This study aims to explore the mechanisms that transgelin participates in the metastasis of colon cancer cells.Methods: Immunofluorescence and immunoblotting analysis were used to determine the cellular localization of the endogenous and exogenous transgelin in colon cancer cells. Co-immunoprecipitation and subsequent high performance liquid chromatography/tandem mass spectrometry were performed to identify the proteins potentially interacting with transgelin. Bioinformatics methods were used to analyze the 256 downstream transcripts regulated by transgelin to discriminate the specific key genes and signaling pathways. By analyzing the promoter region of these key genes, GCBI tools were used to predict the potential transcription factor(s) for these genes. The predicted transcription factors were matching to the proteins that have been identified to potentially interact with transgelin. The interaction between transgelin and these transcription factors was verified by co-immunoprecipitation and immunoblotting.Results: Transgelin was found to localize both in the cytoplasm and the nucleus of colon cancer cells. 297 proteins have been identified to interact with transgelin by co-immunoprecipitation and subsequent high performance liquid chromatography/mass spectrometry. Over-expression of TAGLN could lead to differential expression of 184 downstream genes. By constructing the network of gene-encoded proteins, 7 genes (CALM1, MYO1F, NCKIPSD, PLK4, RAC1, WAS and WIPF1) have been discriminated as key genes using network topology analysis. They are mostly involved in the Rho signaling pathway. Poly ADP-ribose polymerase-1 (PARP1) was predicted as the unique transcription factor for the key genes and concurrently matching to the DNA-binding proteins potentially interacting with transgelin. Immunoprecipitation validated that PARP1 interacted with transgelin in human RKO colon cancer cells.Conclusions: The results of this study suggest that transgelin binds to PARP1 and regulates the expression of the downstream key genes mainly involving Rho signaling pathway, thus participates in the metastasis of colon cancer.

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