Role Of SATB2 Research Articles

The role of SATB2, CDX2, CK7 and CK20 in differentiating primary versus metastatic ovarian carcinoma

The role of SATB2, CDX2, CK7 and CK20 in differentiating primary versus metastatic ovarian carcinoma

Role of SATB2 5' Untranslated Region Promoter Methylation in Formation of Non-syndromic Cleft Palate Only

Role of SATB2 5' Untranslated Region Promoter Methylation in Formation of Non-syndromic Cleft Palate Only

35. CELL-TYPE-SPECIFIC PATTERNS OF DNA METHYLATION IN THE DEVELOPING HUMAN BRAIN

Matrix attachment region (MAR)-binding protein (MARBP) has profound influence on gene transcriptional control by tethering genes to the nuclear scaffold. MARBP SATB2 is recently known as a versatile regulator functioning in the differentiation of multiple cell types including embryonic stem cells, osteoblasts and immunocytes. Roles of SATB2 in erythroid cells and its working mechanism in orchestrating target gene expression are largely unexplored. We show here that SATB2 is expressed in erythroid cells and activates γ-globin genes by binding to MARs in their promoters and recruiting histone acetylase PCAF. Further analysis in higher-order chromatin structure shows that SATB2 affects physical proximity of human Gγ- and Aγ-globin promoters via self-association. We also found that SATB2 interacts with SATB1, which specifically activates ϵ-globin gene expression. Our results establish SATB2 as a novel γ-globin gene regulator and provide a glimpse of the differential and cooperative roles of SATB family proteins in modulating clustered genes transcription and mediating higher-order chromatin structures.

The role of Satb2 in neuronal cell homeostasis

The role of Satb2 in neuronal cell homeostasis

Abstract 4403: Regulation of SATB2 via miR-31 in Ni-induced malignant cell transformation

Abstract The special AT-rich DNA binding protein (SATB2) is a nuclear matrix associated protein and an important transcription factor for biological development, gene regulation, and chromatin remodeling. Under normal circumstances, SATB2 is not expressed in most cells, including epithelial cells of the lung. However, aberrant regulation of SATB2 has been found in various types of cancers including lung, colon, prostate, breast, gastric, and liver. Emerging studies have linked the possible role of SATB2 in carcinogenic metal-induced cell transformation. In fact, our previous microarray analysis showed that SATB2 is strongly induced in Ni-transformed cells. As an IARC Class I Human Carcinogen, there is well-established link between chronic nickel exposure and lung cancer; however, despite of considerable research efforts in regards to the epigenetic mechanisms, little is known about the role of microRNAs in Ni-induced carcinogenesis. As post-transcriptional regulators, miRNAs have great importance in maintaining normal cellular development. In particular, miR-31 is one of the most abundant types of miRNAs and commonly studied in disease development, including cancers of the lung, breast, and liver. Previous studies have shown the miR-31 can directly target the homeobox gene SATB, and here we report that miR-31 is capable of regulating SATB2 in Ni-induced tumorigenesis. First, our results confirmed that knocking down SATB2 in Ni-transformed BEAS-2B cells via shRNA significantly reduced the rate of migration, anchorage-independent growth. Notably, compared to scramble control shRNA transfected cells, SATB2 knockdown cells did not generate tumor growth in mice xenograft model. These results highlight the oncogenic role of SATB2 in cell transformation. In addition, our data indicate that both acute Ni-treated and Ni-transformed cells demonstrated significant reduction in miR-31 expression. Furthermore, we show that overexpressing miR-31 in Ni-transformed cells reduced rates of migration, anchorage-independent growth, and cellular invasion, indicating the importance of miR-31 in Ni-induced BEAS-2B cell transformation. Together, our results provide a novel mechanistic pathway for Ni-induced carcinogenesis, and add to the pool of existing research on the implications of SATB2 and miR-31 in tumorigenesis. Citation Format: Qiao Yi Chen, Yusha Zhu, Ashley Jordan, Jinquan Li, Hong Sun, Thomas Kluz, Max Costa. Regulation of SATB2 via miR-31 in Ni-induced malignant cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4403.

The role of SATB2 and NRG1 as upstream regulatory genes in uterine leiomyomas

As demonstrated in recent direct reprogramming studies, cell specificity or pathogenesis of diseases is determined by a few key upstream regulators. We hypothesized that the aberrant expression of upstream regulatory genes is associated with the onset and development of uterine leiomyomas by altering the expression of the downstream genes. Basic research In order to extract the upstream regulatory genes, Ingenuity Pathway Analysis (IPA) was performed using the transcriptome data of uterine leiomyomas. By IPA analysis, SATB2 and NRG1 were extracted as candidates of upstream regulatory genes. To clarify the function of those genes as upstream regulators, SATB2- and NRG1- overexpressing cells were established using human uterine smooth muscle cells, and transcriptome analysis and KEGG pathway analysis were performed. The result of the KEGG pathway analysis in the cells was compared with that in uterine leiomyomas. In SATB2- and NRG1-overexpressing cells, the expression statuses of 566 and 626 genes (transcriptome analysis), and 92 and 58 pathways (KEGG pathway analysis) were altered, respectively. When these pathways were compared with the pathway that is actually activated in uterine leiomyomas, 63 (68%) and 33 (57%) pathways were activated in SATB2- and NRG1-overexpressing cells, respectively, as well as in uterine leiomyomas. WNT/β-catenin and TGF-β signalings, which are characteristic of uterine leiomyomas, were activated in both overexpressing cells. Furthermore, in SATB2-overexpressing cells, growth factor signalings including VEGF, PDGF and IGF1 were activated as well as uterine leiomyomas. In NRG1-overexpressing cells, retinoic acid signaling was activated as well as uterine leiomyomas. These signalings are also characteristic of uterine leiomyomas. These results indicated that a number of pathways, which are involved in the onset and development of uterine leiomyomas, are activated in SATB2- and NRG1-overexpressing cells. SATB2 and NRG1 are the upstream regulatory genes in uterine leiomyomas. Aberrant expression of SATB2 and NRG1 is associated with the onset and development of uterine leiomyomas by inducing the aberrant expression of the downstream genes, which are associated with WNT/β-catenin, TGF-β, growth factor and retinoic acid signalings.

Abstract 698: The loss of SATB2 promotes ulcerative colitis-related colon cancer progression through altered localized inflammatory response

Abstract SATB2 is a member of a family of special AT-rich binding proteins and a novel transcription factor that orchestrates gene expression in a tissue-specific manner by regulating higher-order chromatin structure. Here, we assess the precise functional role of SATB2 in the development and progression of colorectal cancer, initiating from the proinflammatory phenotype. Differential expression of SATB2 was observed in colorectal cancer, with loss of expression occurring sequentially along the adenoma-carcinoma sequence, with the early preneoplastic tissue demonstrating highest SATB2 levels, which diminishes within adenomas followed by complete loss of SATB2 expression in metastatic disease. Functionally, we demonstrate that siRNA-mediated knockdown of SATB2 in SW480 cells was associated with the acquisition of an aggressive phenotype. Consistent with these findings, loss of SATB2 protein and mRNA expression was determined as an independent predictor of poor prognosis in 3 independent CRC cohorts (n=776). Furthermore, gene set enrichment analysis in two of these independent colorectal cancer cohorts revealed that loss of SATB2 mRNA expression was associated with a TH2 cytokine response and checkpoint genes like CTLA4 and PD1 and modulation of SATB2 expression in CRC cell lines led to altered expression of proinflammatory cytokines. Within this context, following classification of the patient samples within these cohorts into the recently published consensus molecular subtypes (CMS) revealed that SATB2 levels were significantly lower in the CMS1 subtype that effectively represents the immune subtype of colorectal cancer. In addition, tissue microarray (TMA) analysis of a sigmoidal colorectal cancer TMA representing 350 colorectal cancer patients demonstrated that lower SATB2 levels with poor outcome and inversely correlated with CD68+ infiltrates. Intriguingly, SATB2 expression was associated with chromosomal stability as knockdown of SATB2 resulted in an increase of anaphase bridging, which was independent of telomere length and directly related to the spindle assembly complex. Given the relationship between SATB2, chromosomal instability and local inflammatory response, SATB2 protein expression was assessed in a large cohort of patients with ulcerative colitis (UC), some of whom developed UC-related carcinoma. SATB2 protein expression decreased across the disease spectrum from normal to UC to dysplasia to carcinoma, suggesting that SATB2 expression can be used to monitor UC patients at risk of developing CRC. The findings from this study for the first time demonstrate the role of SATB2 as potential master immune-regulator in colon cancer and its pivotal role in regulating key inflammatory factors facilitating the progression of colorectal cancer initiating from a proinflammatory phenotype. Citation Format: Sudipto Das, Kirsha Naicker, Rut Klinger, Yue Fan, Girish Mallya, Fredrick Ponten, Karin Jirström, Jacintha O'Sullivan, William M. Gallagher, Donal J. Brenan, Darran P. O'Connor. The loss of SATB2 promotes ulcerative colitis-related colon cancer progression through altered localized inflammatory response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 698.

The Role of SATB2 as a Diagnostic Marker of Sinonasal Intestinal-type Adenocarcinoma.

Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with exposure to wood and leather dust, nickel, and possibly smoking. ITAC shares phenotypical features with colorectal carcinoma. In contrast to most non-intestinal-type sinonasal adenocarcinomas, ITAC is an aggressive adenocarcinoma with poor clinical outcome; therefore, its reliable separation from non-ITAC is very important. The use of a combination of immunohistochemical markers of intestinal differentiation was tested in a cohort of sinonasal carcinomas of different types. The aim of this study was to explore a new intestinal marker, SATB2, in conjunction with CDX2 and CK20 in differential diagnosis of sinonasal adenocarcinomas. Seven ITACs, 66 non-ITACs, and 1 case of extensive intestinal metaplasia (IM) of the nasal mucosa were included in the study and stained with SATB2, CK20, CDX2, and CK7 antibodies. Detection of mismatch repair proteins was performed in all cases of ITAC. All 7 sinonasal ITACs have been tested for KRAS, NRAS, and BRAF gene mutations. All ITACs showed positive expression for SATB2, whereas all non-ITAC cases were negative. The only 1 case of IM was found to be positive for SATB2, whereas the same case showed negative expression of CK20 and only focal immunostaining for CDX2. The genetic analysis showed that only 1 sinonasal ITAC (1/7) showed KRAS c.35G>C, p.(Gly12Ala) mutation, whereas BRAF and NRAS genes were wild type. Four ITACs revealed wild-type KRAS, NRAS, and BRAF, and 2 remaining cases were not analyzable. All ITACs showed preserved nuclear expression of mismatch repair proteins. SATB2 in combination with CDX2 and CK20 differentiates sinonasal ITAC from non-ITAC with increased diagnostic sensitivity and specificity and detects IM in the sinonasal tract more easily.

Satb2 Ablation Impairs Hippocampus-Based Long-Term Spatial Memory and Short-Term Working Memory and Immediate Early Genes (IEGs)-Mediated Hippocampal Synaptic Plasticity.

Special AT-rich sequence-binding protein 2 (Satb2) is a protein binding to the matrix attachment regions of DNA and important for gene regulation. Patients with SATB2 mutation usually suffer moderate to severe mental retardation. However, the mechanisms for the defects of intellectual activities in patients with SATB2 mutation are largely unclear. Here we established the heterozygous Satb2 mutant mice and Satb2 conditional knockout mice to mimic the patients with SATB2 mutation and figured out the role of Satb2 in mental activities. We found that the spatial memory and working memory were significantly damaged in the heterozygous Satb2 mutant mice, early postnatal Satb2-deficient mice (CaMKIIα-Cre+Satb2fl/fl mice), and adult Satb2 ablation mice (Satb2fl/fl mice injected with CaMKIIα-Cre virus). Functionally, late phase long-term potentiation (L-LTP) in these Satb2 mutant mice was greatly impaired. Morphologically, in CA1 neurons of CaMKIIα-Cre+Satb2fl/fl mice, we found decreased spine density of the basal dendrites and less branches of apical dendrites that extended into lacunar molecular layer. Mechanistically, expression levels of immediate early genes (IEGs) including Fos, FosB, and Egr1 were significantly decreased after Satb2 deletion. And, Satb2 could regulate expression of FosB by binding to the promoter of FosB directly. In general, our study uncovers that Satb2 plays an important role in spatial memory and working memory by regulating IEGs-mediated hippocampal synaptic plasticity.

SATB1 and 2 in colorectal cancer.

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.

The Role of SATB2 as a Diagnostic Marker for Tumors of Colorectal Origin

Immunohistochemistry is an important extension to clinical information and morphology, and prevails as an invaluable tool for establishing a correct cancer diagnosis in clinical diagnostic pathology. The applicability of immunohistochemistry is limited by the availability of validated cell- and cancer-type specific antibodies, rendering an unmet need to discover, test, and validate novel markers. The SATB2 protein is selectively expressed in glandular cells from the lower gastrointestinal tract and expression is retained in a large majority of primary and metastatic colorectal cancers. We analyzed the expression of SATB2 in all clinical cases (n = 840), in which immunohistochemistry for detection of CK20 was deemed necessary for a final diagnosis. SATB2 showed a high sensitivity (93%) and specificity (77%) to determine a cancer of colorectal origin and in combination with CK7 and CK20, the specificity increased to 100%. We conclude that SATB2 provides a new and advantageous supplement for clinical differential diagnostics.

The AT-rich DNA-binding Protein SATB2 Promotes Expression and Physical Association of Human Gγ- and Aγ-Globin Genes

Matrix attachment region (MAR)-binding protein (MARBP) has profound influence on gene transcriptional control by tethering genes to the nuclear scaffold. MARBP SATB2 is recently known as a versatile regulator functioning in the differentiation of multiple cell types including embryonic stem cells, osteoblasts and immunocytes. Roles of SATB2 in erythroid cells and its working mechanism in orchestrating target gene expression are largely unexplored. We show here that SATB2 is expressed in erythroid cells and activates γ-globin genes by binding to MARs in their promoters and recruiting histone acetylase PCAF. Further analysis in higher-order chromatin structure shows that SATB2 affects physical proximity of human (G)γ- and (A)γ-globin promoters via self-association. We also found that SATB2 interacts with SATB1, which specifically activates ε-globin gene expression. Our results establish SATB2 as a novel γ-globin gene regulator and provide a glimpse of the differential and cooperative roles of SATB family proteins in modulating clustered genes transcription and mediating higher-order chromatin structures.

Roles of SATB2 in Osteogenic Differentiation and Bone Regeneration

Expressed in branchial arches and osteoblast-lineage cells, special AT-rich sequence-binding protein (SATB2) is responsible for preventing craniofacial abnormalities and defects in osteoblast function. In this study, we transduced SATB2 into murine adult stem cells, and found that SATB2 significantly increased expression levels of bone matrix proteins, osteogenic transcription factors, and a potent angiogenic factor, vascular endothelial growth factor. Using an osterix (Osx) promoter-luciferase construct and calvarial cells isolated from runt-related transcription factor 2 (Runx2)-deficient mice, we found that SATB2 upregulates Osx expression independent of Runx2, but synergistically enhances the regulatory effect of Runx2 on Osx promoter. We then transplanted SATB2-overexpressing adult stem cells genetically double-labeled with bone sialoprotein (BSP) promoter-driven luciferase and β-actin promoter-driven enhanced green fluorescent protein into mandibular bone defects. We identified increased luciferase-positive cells in SATB2-overexpressing groups, indicating more transplanted cells undergoing osteogenic differentiation. New bone formation was consequently accelerated in SATB2 groups. In conclusion, SATB2 acts as a potent transcription factor to enhance osteoblastogenesis and promote bone regeneration. The application of SATB2 in bone tissue engineering gives rise to a higher bone forming capacity as a result of multiple-level amplification of regulatory activity.

Abstract 1423: SatB2, targeted by miR31, is a modulator in cancer microenvironment

Abstract Cancer growth and metastasis involve an active interaction between primary tumor cells and the tumor's microenvironment, which consists of fibroblasts, vascular cells and inflammatory cells. Such interactions between the cancer and the cells within the microenvironment induce differential expression of genes that act to foster the growth, invasion and spread of tumor cells. This study utilizes pair-wise primary cultures of fibroblasts from normal and cancerous human endometrial tissues of the same patients to investigate the potential factors in the tumor microenvironment and their role in carcinogenesis. Both microRNA and mRNA profiling were performed on paired normal and cancer fibroblasts. SatB2 emerged as a promising candidate when its expression was shown to be significantly increased in fibroblasts surrounding the tumor tissues in all but one patients tested (n=8). Further investigation documented that SatB2 is a target for miR31, via 2 binding sites located within the SATB2 3’ UTR region. In concordance, miR31 is down-regulated in tumor fibroblasts, which further implicates the potential role of SatB2 in promoting a favorable environment for tumors. Ectopic expression of SATB2 in normal fibroblasts does not affect the growth rate of an endometrial cancer cell line (EC-1) in co-culture experiments; however, it did increase the motility of EC-1 cells towards these fibroblasts by multiple folds in both in vitro migration and invasion assays. A reduction of SATB2 expression in cancer activated fibroblasts (CAFs) by shRNA attenuated the migratory ability of EC-1 cells, further supporting the role of SatB2 in tumor aggression. Our observations also indicated that the conditioned media from CAFs were sufficient to induce the motility changes in the EC-1 cells. We believe the elucidation of SatB2 pathway(s) will assist in uncovering the intricate connections between tumors and their microenvironments, leading to new targets for treating tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1423.