Research IndicatorsGraph generated 25 June 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: SATB1 (cancer-related)
The special AT-rich sequence-binding proteins 1 and 2 (SATB1/2) are nuclear matrix associated proteins that are transcription factors involved in chromatin remodeling and gene regulation. Expression of the SATB2 gene is tissue-specific, and the only epithelial cells expressing SATB2 are the glandular cells of the lower gastrointestinal tract where its expression is regulated by microRNA-31 (miR-31) and miR-182. SATB2, along with its homolog SATB1, are thought to be involved in various cancers with their roles in this disease being specific to the type of cancer. Colorectal cancer (CRC) provides the largest association of SATB2 with cancer and the roles of SATB2 are better defined and more studied in CRC than in any other cancer type. SATB1 displays a negative association with SATB2 in CRC. The various studies that have investigated the involvement of SATB1 and 2 in CRC have produced consistent findings. Here, we form four major conclusions regarding the role of these proteins in CRC and their potential clinical value: (i) SATB2 is a sensitive marker to distinguish CRC from other cancer types, (ii) Reduced expression of SATB2 in CRC is associated with poor prognosis, (iii) High levels of SATB1 expression facilitate CRC and are associated with poor prognosis and (iv) Overexpression of miR-31 and -182 in CRC leads to more aggressive cancer. This review will describe several of the key investigations that established these conclusions and highlight results that offer opportunities for future research in the treatment and diagnosis of CRC.
In a previous study, we found that the global genome organizer Special AT-rich binding protein 1 (SATB1) is highly expressed in mesenchymal-derived human osteosarcoma U2OS cells and that the knock-down of SATB1 results in the inhibition of cell proliferation. The present study was aimed at investigating the effect of silencing SATB1 on cell migration, invasion, apoptosis and resistance to the chemotherapeutic drug arsenic trioxide. Cell migration and invasion were detected by wound-healing assays and trans-well invasion assays, respectively. Cell apoptosis was analyzed by an in situ Cell Death Detection POD Kit, based on terminal deoxynucleotydyl transferase mediated dUTP nick-end labeling (TUNEL) staining and mRNAs were analyzed by real time qRT-PCR. We found that cell migration and invasion were inhibited and that the proportion of apoptotic cells and sensitivities to the chemotherapeutic drug arsenic trioxide were enhanced by knockdown of SATB1 in U2OS cells. Furthermore, mRNA of ABCC1 and ABCG2 were decreased strikingly after SATB1 silencing. It was concluded that the elevated expression of SATB1 in U2OS cells contributes to maintenance of the malignant phenotype and resistance to chemotherapeutic drugs ATO, suggesting that silencing SATB1 in the cells might improve the effects of arsenic trioxides in the treatment of osteosarcoma in which SATB1 is over-expressed and that ABCC1 and ABCG2 were involved in SATB1 mediated resistance of U2OS cells to ATO.
Deng YF, Zhou DN, Pan ZY, Yin PAberrant SATB1 expression is associated with Epstein-Barr virus infection, metastasis and survival in human nasopharyngeal cells and endemic nasopharyngeal carcinoma.
Int J Clin Exp Pathol. 2014; 7(5):2454-61 [PubMed
] Free Access to Full Article Related Publications
Special AT-rich sequence-binding protein 1 (SATB1) has been identified as a key factor in the progression of some cancers, functioning as a global genome organizer and chromatin regulator. We examined the levels of SATB1 mRNA expression in NPC cell lines 5-8F (high metastasis) and 6-10B (low metastasis) and immortalized human nasopharyngeal epithelial cells NP69-SV40T by quantitative real-time PCR. We also examined the protein expression levels of SATB1 in 72 cases of nasopharyngeal carcinoma (NPC) tissues and 30 cases of normal nasopharyngeal (NNP) tissues by immunohistochemistry, and then assessed the correlations between SATB1 expression and clinicopathological factors. The expression level of SATB1 mRNA in 5-8F was much higher than those in 6-10B and NP69-SV40T (P<0.05). The expression level of SATB1 mRNA in 6-10B was higher than in NP69-SV40T, but the difference was not statistically significant (P>0.05). The positive expression rates of SATB1 protein in NPC (38/72, 52.8%) were significantly higher than in NNP (4/30, 13.3%) (P<0.05). SATB1 protein levels in NPC were not associated with gender, age, and T stage (P>0.05), but positively correlated with the titers of EBVCA-IgA, metastasis (N and M stage), recurrence, and survival (P<0.05). Multivariate analysis showed that the overexpression of SATB1 protein is an independent prognostic factor for NPC. The expression levels of SATB1 were obviously upregulated in primary NPC tissues and human NPC cell lines. Therefore, SATB1 may be a valuable predictor in assessing the metastasis, recurrence, and prognosis of NPC.
Special AT-rich sequence-binding protein-1 (SATB1) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of SATB1 in RCC remains unclear. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of SATB1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both), and upregulation of SATB1 was significantly associated with depth of invasion (P<0.001), lymph node status (P = 0.001) and TNM stage (P = 0.009). SATB1 knockdown inhibited the proliferation, migration and invasion of 786-O cells, whereas SATB1 overexpression promoted the growth and aggressive phenotype of ACHN cells in vitro. Furthermore, SATB1 expression was positively correlated with ZEB2 expression (P = 0.013), and inversely linked to levels of SATB2 and E-cadherin (P = 0.005 and P<0.001, respectively) in ccRCC tissues. Our data provide a basis for the concept that overexpression of SATB1 may play a critical role in the acquisition of an aggressive phenotype for RCC cells through EMT, providing new insights into the significance of SATB1 in invasion and metastasis of ccRCC, which may contribute to fully elucidating the exact mechanism of development and progression of RCC.
Wang Y, Gu X, Zhang G, et al.SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21.
Blood. 2014; 123(22):3452-61 [PubMed
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Cutaneous CD30(+) lymphoproliferative disease (CD30(+)LPD), characterized by the presence of CD30(+) anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma (CTCL). However, little is known about the pathobiology of the CD30(+) lymphoma cells, as well as the mechanisms of disease progression. Here we report that Special AT-rich region binding protein 1 (SATB1), a thymocyte specific chromatin organizer, is over-expressed in CD30(+) lymphoma cells in most CD30(+)LPDs, and its expression is upregulated during disease progression. Our findings show that SATB1 silencing in CD30(+)LPD cells leads to G1 cell cycle arrest mediated by p21 activation. Using chromatin immunoprecipitation, luciferase assays, and mutational analysis, we demonstrate that SATB1 directly regulates the transcription of p21 in a p53-independent manner. Moreover, DNA demethylation on a specific CpG-rich region of the SATB1 promoter is associated with the upregulation of SATB1 during disease progression. These experiments define a novel SATB1-p21 pathway in malignant CD30(+) T lymphocytes, which provides novel molecular insights into the pathogenesis of CD30(+)LPDs and possibly leads to new therapies.
Frömberg A, Rabe M, Aigner AMultiple effects of the special AT-rich binding protein 1 (SATB1) in colon carcinoma.
Int J Cancer. 2014; 135(11):2537-46 [PubMed
] Related Publications
SATB1 (special AT-rich binding protein 1) is a global chromatin organizer regulating the expression of a large number of genes. Overexpression has been found in various solid tumors and positively correlated with prognostic and clinicopathological properties. In colorectal cancer (CRC), SATB1 overexpression and its correlation with poor differentiation, invasive depth, TNM (tumor, nodes, metastases) stage and prognosis have been demonstrated. However, more detailed studies on the SATB1 functions in CRC are warranted. In this article, we comprehensively analyze the cellular and molecular role of SATB1 in CRC cell lines with different SATB1 expression levels by using RNAi-mediated knockdown. Using siRNAs with different knockdown efficacies, we demonstrate antiproliferative, cell cycle-inhibitory and proapoptotic effects of SATB1 knockdown in a SATB1 gene dose-dependent manner. Tumor growth inhibition is confirmed in vivo in a subcutaneous tumor xenograft mouse model using stable knockdown cells. The in-depth analysis of cellular effects reveals increased activities of caspases-3, -7, -8, -9 and other mediators of apoptotic pathways. Similarly, the analysis of E- and N-cadherin, slug, twist, β-catenin and MMP7 indicates SATB1 effects on epithelial-mesenchymal transition (EMT) and matrix breakdown. Our results also establish SATB1 effects on receptor tyrosine kinases and (proto-)oncogenes such as HER receptors and Pim-1. Taken together, this suggests a more complex molecular interplay between tumor-promoting and possible inhibitory effects in CRC by affecting multiple pathways and molecules involved in proliferation, cell cycle, EMT, invasion and cell survival.
Special AT rich sequence binding protein 1 (SATB1) play an important role in many cancers, but the role of SATB1 in nasopharyngeal carcinoma (NPC) is still not full understand. Immunofluorescence staining showed that SATB1 was mainly localized in the nuclei in CNE-2 cell. After successful down-regulation of SABT1 in NPC cell line CNE-2 by shRNA, compared to parental CNE-2 and control shRNA group, the capacity of the proliferation, migration, invasion and drug resistance of CNE-2 cell was reduced, which indicated that SATB1 may be involved in NPC development and progression. SATB1 may be a promising therapeutic target for nasopharyngeal carcinoma.
Overexpression of special AT-rich sequence binding protein 1 (SATB1), a global genome organizer, as a predictor of poor prognosis in cutaneous malignant melanoma (CMM) attracted great interest in previous research. In this article, upregulated SATB1 was observed in three melanoma cell lines and in eight CMM tissues. After downregulating SATB1 by RNAi, proliferation of A375 was suppressed in vitro and in vivo. In summary, the proliferation of CMM could be related closely to the SATB1 gene. Interference of this gene may be a promising method for CMM therapy.
Chu SH, Zhou ZM, Feng DF, Ma YBInhibition of human glioma U251 cells growth in vitro and in vivo by hydroxyapatite nanoparticle-assisted delivery of short hairpin RNAs against SATB1.
Mol Biol Rep. 2014; 41(2):977-86 [PubMed
] Related Publications
Special AT-rich sequence-binding protein-1 (SATB1) has been reported to be over-expressed in many human tumors and knockdown of SATB1 can inhibit tumor growth. The present study was designed to determine the role of SATB1 in the growth of human glioma U251 cells using the plasmid-based SATB1 short hairpin RNA (shRNA) delivered by hydroxyapatite nanoparticles in vitro and in vivo. The in vitro growth, invasion and angiogenesis assays of human glioma U251 cells were done. U251 cells tumor blocks were transplanted into the nude mice. CaCl2-modified hydroxyapatite nanoparticles carrying shRNA-SATB1 plasmids were injected into the tumors. The apoptosis of the tumor U251 cells was examined with TUNEL assay and flow cytometer (FCM). The tumor growth and immunohistochemistry were measured. The expression level of SATB1 mRNA was investigated by RT-PCR. The expression levels of SATB1, Cyclin D1, MMP-2, VEGF, Bax and Caspase-9 protein were determined by western blot analysis. The results showed that hydroxyapatite nanoparticles-delivered shRNA-SATB1 could significantly inhibit the growth, invasion and angiogenesis of U251 cells in vitro and the growth of U251 cells in vivo. FCM results showed that Nano HAP-shRNA-SATB1-induced apoptosis (up to 67.8 %). SATB1 expression was strongly down-regulated in the tumor U251 cells. Cyclin D1, MMP-2 and VEGF were also down-regulated in the tumor tissues that also displayed significant increased in Bax expression and Caspase-9 activity. These results show that Nano HAP-shRNA-SATB1 can inhibit the growth of human glioma U251 cells in vitro and in vivo, and hydroxyapatite nanoparticles can be used for the in vitro and in vivo delivery of plasmid-based shRNAs into U251 cells.
We recently found that aberrant DNA hypomethylation is more common on the X chromosome than on other chromosomes in uterine leiomyomas by genome-wide DNA methylation profiling. To investigate the mechanism of aberrant hypomethylation on the X chromosome in uterine leiomyomas, we analyzed methylome and transcriptome data from three cases of leiomyomas and the adjacent myometrium. We found that eleven of the aberrantly hypomethylated genes on the X chromosome were common to the three cases. None of these 11 genes were transcriptionally upregulated in the leiomyoma. However, one of them, TSPYL2, was hypomethylated in 68% of multiple leiomyoma specimens. The incidence of aberrant hypomethylation of TSPYL2 was comparable to that of the MED12 mutation (68%), which is known to be detected at a high frequency in uterine leiomyomas. We also analyzed the aberration of the X chromosome inactivation (XCI) mechanism in uterine leiomyomas. Hypomethylation was not enriched in the imprinted genes, suggesting that dysfunction of polycomb repressive complexes is not involved in the aberrant hypomethylation on the X chromosome. The expression analysis of XCI-related genes revealed that the XIST and SATB1 expression was downregulated in 36% and 46% of 11 leiomyoma specimens, respectively, while the HNRNPU and SMCHD1 expression was not altered. In conclusion, the aberration of XCI-related genes such as SATB1 or XIST may be involved in aberrant hypomethylation on the X chromosome in a certain population of the patients with uterine leiomyomas. TSPYL2 of the aberrantly hypomethylated genes on the X chromosome can be used as a biomarker of uterine leiomyomas.
Plakoglobin (γ-catenin) is a homolog of β-catenin with dual adhesive and signaling functions. Plakoglobin participates in cell-cell adhesion as a component of the adherens junction and desmosomes whereas its signaling function is mediated by its interactions with various intracellular protein partners. To determine the role of plakoglobin during tumorigenesis and metastasis, we expressed plakoglobin in the human tongue squamous cell carcinoma (SCC9) cells and compared the mRNA profiles of parental SCC9 cells and their plakoglobin-expressing transfectants (SCC9-PG). We observed that the mRNA levels of SATB1, the oncogenic chromatin remodeling factor, were decreased approximately 3-fold in SCC9-PG cells compared to parental SCC9 cells. Here, we showed that plakoglobin decreased levels of SATB1 mRNA and protein in SCC9-PG cells and that plakoglobin and p53 associated with the SATB1 promoter. Plakoglobin expression also resulted in decreased SATB1 promoter activity. These results were confirmed following plakoglobin expression in the very low plakoglobin expressing and invasive mammary carcinoma cell line MDA-MB-231 cells (MDA-231-PG). In addition, knockdown of endogenous plakoglobin in the non-invasive mammary carcinoma MCF-7 cells (MCF-7-shPG) resulted in increased SATB1 mRNA and protein. Plakoglobin expression also resulted in increased mRNA and protein levels of the metastasis suppressor Nm23-H1, a SATB1 target gene. Furthermore, the levels of various SATB1 target genes involved in tumorigenesis and metastasis were altered in MCF-7-shPG cells relative to parental MCF-7 cells. Finally, plakoglobin expression resulted in decreased in vitro proliferation, migration and invasion in different carcinoma cell lines. Together with the results of our previous studies, the data suggests that plakoglobin suppresses tumorigenesis and metastasis through the regulation of genes involved in these processes.
Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene regulator, and high expression of SATB1 is associated with progression and poor prognosis in several malignancies. Here, we examine the expression pattern of SATB1 in glioma. Microarray analysis of 127 clinical samples showed that SATB1 mRNA was expressed at lower levels in highly malignant glioblastoma multiforme (GBM) than in low-grade glioma and normal brain tissue. This result was further confirmed by real-time RT-PCR in the clinical samples, three GBM cell lines, primary SU3 glioma cells and tumor cells harvested by laser-capture microdissection. Consistent with the mRNA levels, SATB1 protein expression was downregulated in high-grade glioma, as shown by western blotting. However, phospho-SATB1 levels showed an opposite pattern, with a significant increase in these tumors. Immunohistochemical analysis of phospho-SATB1 expression in tissue microarrays with tumors from 122 glioma cases showed that phospho-SATB1 expression was significantly associated with high histological grade and poor survival by Kaplan-Meier analysis. In vitro transfection analysis showed that phospho-SATB1 DNA binding has a key role in regulating the proliferation and invasion of glioma cells. The effect of SATB1 in glioma cell is mainly histone deacetylase (HDAC1)-dependent. We conclude that phospho-SATB1, but not SATB1 mRNA expression, is associated with the progression and prognosis of glioma. By interaction with HDAC1, phospho-SATB1 contributes to the invasive and proliferative phenotype of GBM cells.
Shen Z, Zeng Y, Guo J, et al.Over-expression of the special AT rich sequence binding protein 1 (SATB1) promotes the progression of nasopharyngeal carcinoma: association with EBV LMP-1 expression.
J Transl Med. 2013; 11:217 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Special AT rich sequence binding protein 1 (SATB1) plays a crucial role in the biology of various types of human cancer. However, the role of SATB1 in human nasopharyngeal carcinoma (NPC) remains unknown. In the present study, we sought to investigate the contribution of aberrant SATB1 expression in the progression of NPC and its association with the Epstein Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1).
METHODS: Immunohistochemical analysis was performed to detect SATB1 and LMP-1 protein in clinical samples, and the association of SATB1 protein expression with patient clinicopathological characteristics and LMP-1 expression were analyzed. SATB1 expression profiles were evaluated in well-differentiated NPC cell line CNE1, poorly-differentiated CNE2Z, undifferentiated C666-1 and immortalized nasopharyngeal epithelia NP-69 cells using quantitative RT-PCR, western blotting and fluorescent staining. After inhibition the SATB1 expression by using SATB1 specific small interfering RNA in these cell lines, the change of cell proliferation was investigated by western blotting analysis of PCNA (proliferating cell nuclear antigen) expression and CCK-8 assay, and the cell migration was assessed by Transwell migration assay. Finally, the expressions of SATB1 and PCNA were examined in CNE1 cells that forced LMP-1 expression by fluorescent staining and RT-PCR.
RESULTS: Immunohistochemical analysis revealed that SATB1 protein expression was elevated in NPC tissues compared to benign nasopharyngeal tissues (P = 0.005). Moreover, high levels of SATB1 protein expression were positively correlated with clinical stage (P = 0.025), the status of lymph node metastasis (N classification) (P = 0.018), distant metastasis (M classification) (P = 0.041) and LMP-1 expression status (r = 2.35, P < 0.01) in NPC patients. In vitro experiments demonstrated that an inverse relationship between SATB1 expression and NPC differentiation status, with SATB1 weakly expressed in NP-69 cells and CNE1 cells, and significant increasingly expressed in CNE-2Z and C666-1 cells. Targeted knockdown of SATB1 expression obviously attenuated the proliferation and migration of highly SATB1-expressing CNE2Z and C666-1 cells, but not NP-69 and CNE1 cells. Interestingly, forced LMP-1 expression in CNE1 cells led to a surprisingly increasing SATB1 expression and nuclear location, companying with an up-regulated PCNA expression.
CONCLUSIONS: Our results reveal that EBV LMP-1-mediated over-expression of SATB1 is associated with NPC progression, suggesting SATB1 may represent a promising biomarker and therapeutic target for NPC.
BRIP1 is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1 and plays an important role in BRCA1-dependent DNA repair and DNA damage-induced checkpoint control. Recent studies implicate BRIP1 as a moderate/low-penetrance breast cancer susceptibility gene. However, the phenotypic effects of BRIP1 dysfunction and its role in breast cancer tumorigenesis remain unclear. To explore the function of BRIP1 in acinar morphogenesis of mammary epithelial cells, we generated BRIP1-knockdown MCF-10A cells by short hairpin RNA (shRNA)-mediated RNA interference and examined its effect in a three-dimensional culture model. Genome-wide gene expression profiling by microarray and quantitative RT-PCR were performed to identify alterations in gene expression in BRIP1-knockdown cells compared with control cells. The microarray data were further investigated using the pathway analysis and Gene Set Enrichment Analysis (GSEA) for pathway identification. BRIP1 knockdown in non-malignant MCF-10A mammary epithelial cells by RNA interference induced neoplastic-like changes such as abnormal cell adhesion, increased cell proliferation, large and irregular-shaped acini, invasive growth, and defective lumen formation. Differentially expressed genes, including MCAM, COL8A1, WIPF1, RICH2, PCSK5, GAS1, SATB1, and ELF3, in BRIP1-knockdown cells compared with control cells were categorized into several functional groups, such as cell adhesion, polarity, growth, signal transduction, and developmental process. Signaling-pathway analyses showed dysregulation of multiple cellular signaling pathways, involving LPA receptor, Myc, Wnt, PI3K, PTEN as well as DNA damage response, in BRIP1-knockdown cells. Loss of BRIP1 thus disrupts normal mammary morphogenesis and causes neoplastic-like changes, possibly via dysregulating multiple cellular signaling pathways functioning in the normal development of mammary glands.
Tumor cells of classical Hodgkin lymphoma (cHL) are characterized by a general loss of B cell phenotype, whereas antigen presenting properties are commonly retained. HLA class I is expressed in most EBV+ cHL cases, with an even enhanced expression in a proportion of the cases. Promyelocytic leukemia protein (PML) and special AT-rich region binding protein 1 (SATB1) are two global chromatin organizing proteins that have been shown to regulate HLA class I expression in Jurkat cells. We analyzed HLA class I, number of PML nuclear bodies (NBs) and SATB1 expression in tumor cells of 54 EBV+ cHL cases and used 27 EBV- cHL cases as controls. There was a significant difference in presence of HLA class I staining between EBV+ and EBV- cases (p<0.0001). We observed normal HLA class I expression in 35% of the EBV+ and in 19% of the EBV- cases. A stronger than normal HLA class I expression was observed in approximately 40% of EBV+ cHL and not in EBV- cHL cases. 36 EBV+ cHL cases contained less than 10 PML-NBs per tumor cell, whereas 16 cases contained more than 10 PML-NBs. The number of PML-NBs was positively correlated to the level of HLA class I expression (p<0.01). The percentage of SATB1 positive cells varied between 0% to 100% in tumor cells and was inversely correlated with the level of HLA class I expression, but only between normal and strong expression (p<0.05). Multivariable analysis indicated that the number of PML-NBs and the percentage of SATB1+ tumor cells are independent factors affecting HLA class I expression in EBV+ cHL. In conclusion, both PML and SATB1 are correlated to HLA class I expression levels in EBV+ cHL.
Han B, Luan L, Xu Z, Wu BExpression and biological roles of SATB1 in human bladder cancer.
Tumour Biol. 2013; 34(5):2943-9 [PubMed
] Related Publications
Special AT-rich sequence-binding protein-1 (SATB1) has been recently reported to be overexpressed in various cancers and associate with the malignant behavior of cancer cells. However, the expression and potential roles of SATB1 in bladder cancer remains unclear. In the present study, SATB1 expression was analyzed in 85 archived bladder cancer specimens using immunohistochemistry and the correlations between SATB1 expression and clinicopathological parameters were evaluated. To further explore the biological functions of SATB1 in bladder cancer, siRNA knockdown was performed in 5637 and T24 bladder cancer cell lines. We then carried out CCK8 assay and examined cisplatin-induced apoptosis to address the roles of SATB1 in proliferation and apoptosis. We found that SATB1 was overexpressed in 33 of 85 (38.8 %) bladder cancer specimens. SATB1 overexpression associated with tumor grade (p = 0.002) and tumor stage (p = 0.027). SATB1 depletion in 5637 and T24 cells decreased cell proliferation while upregulating cisplatin-induced apoptosis. Further study demonstrated that SATB1 knockdown decreased cyclin D1 and cyclin E expression and upregulated caspase3 cleavage. In conclusion, SATB1 is overexpressed in bladder cancer and regulates malignant cell growth and apoptosis, which makes SATB1 a therapeutic target candidate for bladder cancer.
Shen Z, Chen L, Yang X, et al.Downregulation of Ezh2 methyltransferase by FOXP3: new insight of FOXP3 into chromatin remodeling?
Biochim Biophys Acta. 2013; 1833(10):2190-200 [PubMed
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Transcription factor FOXP3 (forkhead box P3) is found initially as a key regulator in regulatory T cells. Recently its expression has been demonstrated in some non-lymphoid normal and cancerous cells. Now FOXP3 has been proven to regulate cancer-related genes, especially suppressor genes in breast cancer. But the mechanisms by which FOXP3 regulates suppressor genes are not fully determined. In this study, we found the inverse correlation between FOXP3 and Ezh2, an enzyme for histone H3K27 trimethylation (H3K27me3) and a central epigenetic regulator in cancer. The overexpression of FOXP3 weakened Ezh2's enhancement on the mammosphere formation, cell proliferation, directional migration, and colony forming ability of T47D cells. We demonstrated that FOXP3 could downregulate Ezh2 protein level and this depended on not only the FOXP3 expression amount, but also the nuclear localization of FOXP3. More importantly, we demonstrated FOXP3 accelerated Ezh2 protein degradation through the polyubiquitination-proteasome pathway by enhancing the transcription of E3 ligase Praja1 directly. These results provided a new mechanism for FOXP3 in histone modifications as an Ezh2 suppressor and supported new evidence for FOXP3 as a tumor suppressor in breast cancer.
Tumor progression is associated with invasiveness and metastatic potential. The special AT-rich binding protein 1 (SATB1) has been identified as a key factor in the progression of breast cancer cells to a malignant phenotype and is associated with progression of human tumors. In normal development, SATB1 coordinates gene expression of progenitor cells by functioning as a genome organizer. In contrast to progenitor and tumor cells, SATB1 expression in nontransformed cells is not compatible with proliferation. Here we show that SATB1 expression in mouse embryonic fibroblasts induces cell cycle arrest and senescence that is associated with elevated p16 protein levels. Deletion of p16 overcomes the SATB1-induced senescence. We further provide evidence for an interaction of SATB1 with the retinoblastoma (RB)/E2F pathway downstream of p16. A combined deletion of the RB proteins, RB, p107 and p130 (triple-mutant; TM), prevents SATB1-induced G1 arrest, which is restored upon the reintroduction of RB into SATB1-expressing TM fibroblasts. SATB1 interacts with the E2F/RB complex and regulates the cyclin E promoter in an E2F-dependent manner. These findings demonstrate that p16 and the RB/E2F pathway are critical for SATB1-induced cell cycle arrest. In the absence of p16, SATB1 causes anchorage-independent growth and invasive phenotype in fibroblasts. Our data illustrate that p16 mutations collaborate with the oncogenic activity of SATB1. Consistent with our finding, a literature survey shows that deletion of p16 is generally associated with SATB1 expressing human cell lines and tumors.
BACKGROUND: Special AT-rich sequence binding protein 1 (SATB1) is a nuclear factor that functions as the global chromatin organizer to regulate chromatin structure and gene expression gene expression. SATB1 has been shown to be abnormally expressed in various types of cancer. However, the expression and role of SATB1 in prostate cancer remain unclear.
METHODS: 120 cases of prostatic carcinoma and 60 cases of benign prostate hyperplasia were analyzed for SATB1 expression by immunohistochemistry. LNCaP, DU-145, and PC3 prostate cancer cells were examined for SATB1 expression by Western blot analysis. Cell proliferation and invasion was evaluated by CCK8 and transwell invasion assay, respectively.
RESULTS: SATB1 staining was stronger in prostatic carcinomas with metastasis than in those without metastasis, but was absent in benign prostate hyperplasia. Furthermore, SATB1 expression was positively correlated with bone metastasis and the Gleason score. SATB1 overexpression promoted the proliferation and invasion of LNCaP cells while SATB1 knockdown inhibited the proliferation and invasion of DU-145 cells.
CONCLUSIONS: These findings provide novel insight into oncogenic role of SATB1 in prostate cancer, suggesting that SATB1 is a promising biomarker and therapeutic target for prostate cancer.
AIM: To evaluate the expression of special AT-rich sequence-binding protein 1 (SATB1) gene in colorectal cancer and its role in colorectal cancer cell proliferation and invasion.
METHODS: Immunohistochemistry was used to detect the protein expression of SATB1 in 30 colorectal cancer (CRC) tissue samples and pair-matched adjacent non-tumor samples. Cell growth was investigated after enhancing expression of SATB1. Wound-healing assay and Transwell assay were used to investigate the impact of SATB1 on migratory and invasive abilities of SW480 cells in vitro. Nude mice that received subcutaneous implantation or lateral tail vein were used to study the effects of SATB1 on tumor growth or metastasis in vivo.
RESULTS: SATB1 was over-expressed in CRC tissues and CRC cell lines. SATB1 promotes cell proliferation and cell cycle progression in CRC SW480 cells. SATB1 overexpression could promote cell growth in vivo. In addition, SATB1 could significantly raise the ability of cell migration and invasion in vitro and promote the ability of tumor metastasis in vivo. SATB1 could up-regulate matrix metalloproteases 2, 9, cyclin D1 and vimentin, meanwhile SATB1 could down-regulate E-cadherin in CRC.
CONCLUSION: SATB1 acts as a potential growth and metastasis promoter in CRC. SATB1 may be useful as a therapeutic target for CRC.
Nagpal N, Ahmad HM, Molparia B, Kulshreshtha RMicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer.
Carcinogenesis. 2013; 34(8):1889-99 [PubMed
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Estrogen- and microRNA-mediated gene regulation play a crucial role in breast cancer biology. However, a functional link between the two major players remains unclear. This study reveals miR-191 as an estrogen-inducible onco-miR in breast cancer, which promotes several hallmarks of cancer including enhanced cell proliferation, migration, chemoresistance and survival in tumor microenvironment. miR-191 is a direct estrogen receptor (ER) target and our results suggest existence of a positive regulatory feedback loop. We show miR-191 as critical mediator of estrogen-mediated cell proliferation. Investigations of mechanistic details of miR-191 functions identify several cancer-related genes like BDNF, CDK6 and SATB1 as miR-191 targets. miR-191 and SATB1 show inverse correlation of expression. miR-191-mediated enhanced cell proliferation and migration are partly dependent on targeted downregulation of SATB1. Further, functional validation of estrogen:miR-191:SATB1 link suggests a cascade initiated by estrogen that induces miR-191 in ER-dependent manner to target SATB1, a global chromatin remodeler, thereby contributing to estrogen-specific gene signature to regulate genes like ANXA1, PIWIL2, CASP4, ESR1/ESR2, PLAC1 and SOCS2 involved in breast cancer progression and migration. Overall, the identification of estrogen/ER/miR-191/SATB1 cascade seems to be a significant pathway in estrogen signaling in breast cancer with miR-191 as oncogenic player.
Zhang H, Qu S, Li S, et al.Silencing SATB1 inhibits proliferation of human osteosarcoma U2OS cells.
Mol Cell Biochem. 2013; 378(1-2):39-45 [PubMed
] Related Publications
It has been shown that over-expression of Special AT-rich binding protein 1 (SATB1) in breast cancer predicts a poor prognosis. This study was aimed at investigating the effects of silencing SATB1 on mesenchymal derived human osteosarcoma U2OS cells and the underlying mechanisms. The expressions of SATB1 and the related genes in the cells were detected by qRT-PCR and/or Western Blotting. SATB1 silencing was achieved by stable transfection with the vectors expressing small hairpin RNA versus SATB1. Cell proliferation was detected in a microplate reader with Cell Counting Kit-8 and the cell cycle was analyzed by flow cytometry using a cell cycle detection kit. The study found that SATB1 was particularly over-expressed in human osteosarcoma U2OS. Silencing SATB1 inhibited the proliferation of U2OS. It was found that inhibition of cell proliferation resulted from cell cycle arrest due to down-regulated expression of CFGF and JunB. The over-expression of SATB1 is responsible for abnormal proliferation of mesenchymal derived human Osteosatcoma U2OS cells, indicating that silencing SATB1 expression in the cells might be developed as an efficient osteosarcoma therapy. CTGF and JunB were involved in SATB1-mediated proliferation of U2OS cells.
Di Leva G, Piovan C, Gasparini P, et al.Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status.
PLoS Genet. 2013; 9(3):e1003311 [PubMed
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MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells.
Wang M, Yin B, Matsueda S, et al.Identification of special AT-rich sequence binding protein 1 as a novel tumor antigen recognized by CD8+ T cells: implication for cancer immunotherapy.
PLoS One. 2013; 8(2):e56730 [PubMed
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BACKGROUND: A large number of human tumor-associated antigens that are recognized by CD8(+) T cells in a human leukocyte antigen class I (HLA-I)-restricted fashion have been identified. Special AT-rich sequence binding protein 1 (SATB1) is highly expressed in many types of human cancers as part of their neoplastic phenotype, and up-regulation of SATB1 expression is essential for tumor survival and metastasis, thus this protein may serve as a rational target for cancer vaccines.
METHODOLOGY/PRINCIPAL FINDINGS: Twelve SATB1-derived peptides were predicted by an immuno-informatics approach based on the HLA-A*02 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from HLA-A*02(+) healthy donors and/or HLA-A*02(+) cancer patients. The recognition of HLA-A*02(+) SATB1-expressing cancer cells was also tested. Among the twelve SATB1-derived peptides, SATB1(565-574) frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and cancer patients. Importantly, SATB1(565-574)-specific T cells recognized and killed HLA-A*02(+) SATB1(+) cancer cells in an HLA-I-restricted manner.
CONCLUSIONS/SIGNIFICANCE: We have identified a novel HLA-A*02-restricted SATB1-derived peptide epitope recognized by CD8(+) T cells, which, in turn, recognizes and kills HLA-A*02(+) SATB1(+) tumor cells. The SATB1-derived epitope identified may be used as a diagnostic marker as well as an immune target for development of cancer vaccines.
There is increasing evidence that Special AT-rich sequence-binding protein 1 (SATB1) is aberrantly expressed in several cancers and is correlated with clinicopathologic parameters in these tumors. In this study, we showed over-expression of SATB1 in 80 cases of colorectal cancer and in 3 colorectal cancer cell lines and found expression levels were strongly associated with tumor differentiation and stage. Expression levels of SATB1 protein were higher in poorly-differentiated as compared with well-differentiated cell lines, and both quantity and distribution patterns of SATB1 were associated with tumor differentiation and pTNM stage. Strikingly, we further investigated the effect of down regulation of SATB1 expression on malignant phenotypic features in colorectal cancer cells in vitro, and showed that SABT1 down-regulation negatively affected growth potential, anchorage-independent colony formation and cancer cell invasion, and resulted in increased apoptosis. SATB1 expression was positively associated with the expression of various biological and genetic markers, including Cyclin D1, MMP-2, NF-κB, and PCNA, and was associated with loss of APC and BRAF(V600E). These findings suggest that SATB1 is involved in the carcinogenesis, development and progression of colorectal cancer.
Chu SH, Ma YB, Feng DF, et al.Relationship between SATB1 expression and prognosis in astrocytoma.
J Clin Neurosci. 2013; 20(4):543-7 [PubMed
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Special AT-rich-sequence-binding protein 1 (SATB1), a new type of gene regulator, has been reported to be expressed in various human cancers and may be associated with malignancy. The aim of this study was to investigate the expression of SATB1 in astrocytoma and to determine its prognostic value for the overall survival of patients with astrocytoma. The expression of SATB1 protein and messenger RNA (mRNA) in human astrocytoma specimens was examined using immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The relationship between SATB1 expression and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was also investigated. Spearman's correlation coefficient was used to describe the association between SATB1 expression and the clinical parameters of astrocytoma patients. SATB1 protein and mRNA were expressed at significant levels in astrocytoma specimens. SATB1 expression was positively correlated with astrocytoma pathological grade but negatively correlated with the life span of astrocytoma patients. SATB1 expression was also significantly lower in astrocytoma specimens with MGMT promoter methylation than in those without MGMT promoter methylation. Our findings suggest that SATB1 may have an important role as a positive regulator of astrocytoma development and progression and that SATB1 might be a useful molecular marker for predicting the prognosis of patients with astrocytoma and could be a novel target for treating astrocytoma.
Disease aggressiveness remains a critical factor to the progression of prostate cancer. Transformation of epithelial cells to mesenchymal lineage, associated with the loss of E-cadherin, offers significant invasive potential and migration capability. Recently, Special AT-rich binding protein (SATB1) has been linked to tumor progression. SATB1 is a cell-type restricted nuclear protein, which functions as a tissue-specific organizer of DNA sequences during cellular differentiation. Our results demonstrate that SATB1 plays significant role in prostate tumor invasion and migration and its nuclear localization correlates with disease aggressiveness. Clinical specimen analysis showed that SATB1 was predominantly expressed in the nucleus of high-grade tumors compared to low-grade tumor and benign tissue. A progressive increase in the nuclear levels of SATB1 was observed in cancer tissues compared to benign specimens. Similarly, SATB1 protein levels were higher in a number of prostate cancer cells viz. HPV-CA-10, DU145, DUPro, PC-3, PC-3M, LNCaP and C4-2B, compared to non-tumorigenic PZ-HPV-7 cells. Nuclear expression of SATB1 was higher in biologically aggressive subclones of prostate cancer cells with their respective parental cell lines. Furthermore, ectopic SATB1 transfection conferred increased cell motility and invasiveness in immortalized human prostate epithelial PZ-HPV-7 cells which correlated with the loss of E-cadherin expression. Consequently, knockdown of SATB1 in highly aggressive human prostate cancer PC-3M cells inhibited invasiveness and tumor growth in vivo along with increase in E-cadherin protein expression. Our findings demonstrate that SATB1 has ability to promote prostate cancer aggressiveness through epithelial-mesenchymal transition.
SATB1 drives metastasis when expressed in breast tumor cells by radically reprogramming gene expression. Here, we show that SATB1 also has an oncogenic activity to transform certain non-malignant breast epithelial cell lines. We studied the non-malignant MCF10A cell line, which is used widely in the literature. We obtained aliquots from two different sources (here we refer to them as MCF10A-1 and MCF10A-2), but found them to be surprisingly dissimilar in their responses to oncogenic activity of SATB1. Ectopic expression of SATB1 in MCF10A-1 induced tumor-like morphology in three-dimensional cultures, led to tumor formation in immunocompromised mice, and when injected into tail veins, led to lung metastasis. The number of metastases correlated positively with the level of SATB1 expression. In contrast, SATB1 expression in MCF10A-2 did not lead to any of these outcomes. Yet DNA copy-number analysis revealed that MCF10A-1 is indistinguishable genetically from MCF10A-2. However, gene expression profiling analysis revealed that these cell lines have significantly divergent signatures for the expression of genes involved in oncogenesis, including cell cycle regulation and signal transduction. Above all, the early DNA damage-response kinase, ATM, was greatly reduced in MCF10A-1 cells compared to MCF10A-2 cells. We found the reason for reduction to be phenotypic drift due to long-term cultivation of MCF10A. ATM knockdown in MCF10A-2 and two other non-malignant breast epithelial cell lines, 184A1 and 184B4, enabled SATB1 to induce malignant phenotypes similar to that observed for MCF10A-1. These data indicate a novel role for ATM as a suppressor of SATB1-induced malignancy in breast epithelial cells, but also raise a cautionary note that phenotypic drift could lead to dramatically different functional outcomes.
Elton TS, Selemon H, Elton SM, Parinandi NLRegulation of the MIR155 host gene in physiological and pathological processes.
Gene. 2013; 532(1):1-12 [PubMed
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MicroRNAs (miRNAs), a family of small nonprotein-coding RNAs, play a critical role in posttranscriptional gene regulation by acting as adaptors for the miRNA-induced silencing complex to inhibit gene expression by targeting mRNAs for translational repression and/or cleavage. miR-155-5p and miR-155-3p are processed from the B-cell Integration Cluster (BIC) gene (now designated, MIR155 host gene or MIR155HG). MiR-155-5p is highly expressed in both activated B- and T-cells and in monocytes/macrophages. MiR-155-5p is one of the best characterized miRNAs and recent data indicate that miR-155-5p plays a critical role in various physiological and pathological processes such as hematopoietic lineage differentiation, immunity, inflammation, viral infections, cancer, cardiovascular disease, and Down syndrome. In this review we summarize the mechanisms by which MIR155HG expression can be regulated. Given that the pathologies mediated by miR-155-5p result from the over-expression of this miRNA it may be possible to therapeutically attenuate miR-155-5p levels in the treatment of several pathological processes.
Endo K, Shackelford J, Aga M, et al.Upregulation of special AT-rich-binding protein 1 by Epstein-Barr virus latent membrane protein 1 in human nasopharyngeal cells and nasopharyngeal cancer.
J Gen Virol. 2013; 94(Pt 3):507-13 [PubMed
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A global regulator of chromatin remodelling and gene expression, special AT-rich-binding protein 1 (SATB1) has been implicated in promotion of growth and metastasis of a number of cancers. Here, we demonstrate that the principal oncogene of Epstein-Barr virus (EBV), latent membrane protein 1 (LMP1) upregulates SATB1 RNA and protein expression in human nasopharyngeal cell lines. Silencing of endogenously expressed SATB1 with specific short hairpin RNA decreases cell proliferation and resistance to apoptosis induced by growth factor withdrawal. Additionally, we provide evidence that LMP1-mediated expression of Survivin, a multifunctional protein involved in promoting cell growth and survival, is mediated at least in part by SATB1 in human nasopharyngeal cells. Finally, we show that SATB1 protein levels are elevated in tissue samples from patients with nasopharyngeal carcinoma (NPC), and are directly correlated with the expression of LMP1. Taken together, our results suggest that SATB1 functions as a pro-metastatic effector of LMP1 signalling in EBV-positive NPC.