The miR-641-STIM1 and SATB1 axes play important roles in the regulation of the Th17/Treg balance in ITP.

Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.

SAFB restricts contact domain boundaries associated with L1 chimeric transcription.

Long interspersed element-1 (LINE-1 or L1) comprises 17% of the human genome, continuously generates genetic variations, and causes disease in certain cases. However, the regulation and function of L1 remain poorly understood. Here, we uncover that L1 can enrich RNA polymerase IIs (RNA Pol IIs), express L1 chimeric transcripts, and create contact domain boundaries in human cells. This impact of L1 is restricted by a nuclear matrix protein scaffold attachment factor B (SAFB) that recognizes transcriptionally active L1s by binding L1 transcripts to inhibit RNA Pol II enrichment. Acute inhibition of RNA Pol II transcription abolishes the domain boundaries associated with L1 chimeric transcripts, indicating a transcription-dependent mechanism. Deleting L1 impairs domain boundary formation, and L1 insertions during evolution have introduced species-specific domain boundaries. Our data show that L1 can create RNA Pol II-enriched regions that alter genome organization and that SAFB regulates L1 and RNA Pol II activity to preserve gene regulation.

SATB1 mediated tumor colonization and ß-catenin nuclear localization are associated with colorectal cancer progression.

Colorectal cancer (CRC) is a malignancy with high incidence and poor prognosis. It is urgent to identify valuable biomarkers for early diagnosis and potent therapeutic targets. It has been reported that SATB1 is associated with the malignant progression in CRC. To explore the role of SATB1 in CRC progression and the underlying mechanism, we evaluated the expression of SATB1 in the paired CRC tissues with immunohistochemistry. The results showed that the expression of SATB1 in lymph node metastasis was higher than that in primary lesion, and that in distant organ metastasis was higher than that in primary lesion. The retrospective analysis showed that patients with high expression of SATB1 had a significantly worse prognosis than those with negative and moderate expression. In vitro experiments that employing SATB1 over-expressing and depleted CRC cell lines confirmed that SATB1 contributes to cell proliferation and colonization, while inhibiting cell motility. Furthermore, the tissue immunofluorescence assay, Co-IP and Western blot were conducted to reveal that SATB1 induced translocation of ß-catenin and formed a protein complex with it in the nuclei. In conclusion, SATB1 mediated tumor colonization and ß-catenin nuclear localization are associated with the malignant progression and poor prognosis of CRC.

Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer.

The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.

Progress of epigenetic modification of SATB2 gene in the pathogenesis of non-syndromic cleft lip and palate.

Non-syndromic Cleft Lip and Palate (NSCLP) is one of the most common congenital craniofacial malformations. However, there is no enough knowledge about its mechanism, even through many relevant studies verify that cleft lip and palate is caused by interactions between environmental and genetic factors. SATB2 gene is one of the most common candidate genes of NSCLP, and the development of epigenetics provides a new direction on pathogenesis of cleft lip and palate. This review summarizes SATB2 gene in the pathogenesis of non-syndromic cleft lip and palate, expecting to provide strategies to prevent and treat cleft and palate in the future.

Long non-coding RNA LINC00491 accelerates head and neck squamous cell carcinoma progression through regulating miR-508-3p/SATB1 axis and activating Wnt signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck epidermis. Accumulating long non-coding RNAs (lncRNAs) have been proven to be involved in the occurrence and development of HNSCC. LncRNA long intergenic non-protein coding RNA 491 (LINC00491) has been confirmed to regulate the progression of some cancers. In our study, we aimed to explore the potential biological function of LINC00491 and expound the regulatory mechanism by which LINC00491 affects the progression of HNSCC. RT-qPCR was utilized to analyze the expression of LINC00491 in HNSCC cell lines and the normal cell line. Functionally, we carried out a series of assays to measure cell proliferation, apoptosis, migration and invasion, such as EdU assay, colony formation, wound healing and western blot assays. Also, mechanism assays including RNA pull down and RIP were also implemented to investigate the interaction of LINC00491 and RNAs. As a result, we discovered that LINC00491 was highly expressed in HNSCC cells. In addition, LINC00491 depletion suppressed cell proliferation, migration and EMT process. Furthermore, we discovered that LINC00491 could bind to miR-508-3p. MiR-508-3p overexpression can restrain HNSCC cell growth. Importantly, miR-508-3p can target SATB homeobox 1 (SATB1) in HNSCC cells. Further, Wnt signaling pathway was proved to be activated by LINC00491 through SATB1 in HNSCC cells. In a word, LINC00491 accelerated HNSCC progression through regulating miR-508-3p/SATB1 axis and activating Wnt signaling pathway.

hsa_circ_0010889 downregulation inhibits malignant glioma progression by modulating the miR-590-5p/SATB1 axis.

Glioma is a general neurological tumor and circular RNAs (circRNAs) have been implicated in glioma development. However, the underlying mechanisms and circRNA biological functions responsible for the regulation of glioma progression remain unknown. In this study, we employ next-generation sequencing (NGS) to investigate altered circRNA expression in glioma tissues. Regulatory mechanisms were studied using luciferase reporter analyses, transwell migration, CCK8, and EdU analysis. Tumorigenesis and metastasis assays were utilized to determine the function of hsa_circ_0010889 in glioma. Our results showed that hsa_circ_0010889 expression increased in glioma cell lines and tissues, indicating that hsa_circ_0010889 may be involved in glioma progression. Downregulation of hsa_circ_0010889 inhibited glioma invasion and proliferation in both in vitro and in vivo experiments and luciferase report assays found that miR-590-5p and SATB1 were downstream targets for hsa_circ_0010889. SATB1 overexpression or miR-590-5p inhibition reversed glioma cells proliferation and migration post-silencing of hsa_circ_0010889. Taken together, our study demonstrates that hsa_circ_0010889 downregulation inhibits glioma progression through the miR-590-5p/SATB1 axis.

HDAC5 modulates SATB1 transcriptional activity to promote lung adenocarcinoma.

BACKGROUND: Dysregulation of histone deacetylases has been linked to diverse cancers. HDAC5 is a histone deacetylase belonging to Class IIa family of histone deacetylases. Limited substrate repertoire restricts the understanding of molecular mechanisms underlying its role in tumorigenesis. METHODS: We employed a biochemical screen to identify SATB1 as HDAC5-interacting protein. Coimmunoprecipitation and deacetylation assay were performed to validate SATB1 as a HDAC5 substrate. Proliferation, migration assay and xenograft studies were performed to determine the effect of HDAC5-SATB1 interaction on tumorigenesis. RESULTS: Here we report that HDAC5 binds to and deacetylates SATB1 at the conserved lysine 411 residue. Furthermore, dynamic regulation of acetylation at this site is determined by TIP60 acetyltransferase. We also established that HDAC5-mediated deacetylation is critical for SATB1-dependent downregulation of key tumor suppressor genes. Deacetylated SATB1 also represses SDHA-induced epigenetic remodeling and anti-proliferative transcriptional program. Thus, SATB1 spurs malignant phenotype in a HDAC5-dependent manner. CONCLUSIONS: Our study highlights the pivotal role of HDAC5 in tumorigenesis. Our findings provide key insights into molecular mechanisms underlying SATB1 promoted tumor growth and metastasis.

A monoclonal antibody raised against human EZH2 cross-reacts with the RNA-binding protein SAFB.

The Polycomb Repressive Complex 2 (PRC2) is a conserved enzyme that tri-methylates Lysine 27 on Histone 3 (H3K27me3) to promote gene silencing. PRC2 is remarkably responsive to the expression of certain long noncoding RNAs (lncRNAs). In the most notable example, PRC2 is recruited to the X-chromosome shortly after expression of the lncRNA Xist begins during X-chromosome inactivation. However, the mechanisms by which lncRNAs recruit PRC2 to chromatin are not yet clear. We report that a broadly used rabbit monoclonal antibody raised against human EZH2, a catalytic subunit of PRC2, cross-reacts with an RNA-binding protein called Scaffold Attachment Factor B (SAFB) in mouse embryonic stem cells (ESCs) under buffer conditions that are commonly used for chromatin immunoprecipitation (ChIP). Knockout of EZH2 in ESCs demonstrated that the antibody is specific for EZH2 by western blot (no cross-reactivity). Likewise, comparison to previously published datasets confirmed that the antibody recovers PRC2-bound sites by ChIP-Seq. However, RNA-IP from formaldehyde-crosslinked ESCs using ChIP wash conditions recovers distinct peaks of RNA association that co-localize with peaks of SAFB and whose enrichment disappears upon knockout of SAFB but not EZH2. IP and mass spectrometry-based proteomics in wild-type and EZH2 knockout ESCs confirm that the EZH2 antibody recovers SAFB in an EZH2-independent manner. Our data highlight the importance of orthogonal assays when studying interactions between chromatin-modifying enzymes and RNA.

Crucial Roles of SATB1 in Regulation of Thymocyte Migration after Positive Selection.

Double-positive thymocytes that have passed positive selection migrate from the cortex to the medulla, where negative selection and the development of thymic regulatory T cells (tTregs) take place. Medullary thymic epithelial cells (mTECs) play important roles in these selections, and their differentiation and maintenance depend on interaction with positively selected CD4+ single-positive cells. Therefore, migration and differentiation after positive selection must be coordinated to establish immune tolerance. However, the regulatory mechanisms of these processes are not fully understood. SATB1 is a genome organizer highly expressed in double-positive thymocytes, and SATB1 deletion causes various defects in T-cell development, including impaired positive and negative selection and tTreg differentiation. Here, we show that SATB1 is critical for temporally coordinated thymocyte trafficking after positive selection in mice. Satb1 knockout (ΔSatb1) led to precocious thymic egress caused by augmented S1pr1 upregulation in positively selected thymocytes, accompanied by lower induction of Ccr7, Tnfsf11, and Cd40lg. Altered thymocyte trafficking and functionality affected the differentiation of mTECs and, in turn, tTreg differentiation. Thus, SATB1 is required to establish immune tolerance, at least in part, by ensuring timely thymic egress and mTEC differentiation.

microRNA-660 Enhances Cisplatin Sensitivity via Decreasing SATB2 Expression in Lung Adenocarcinoma.

Increasing evidence suggests that microRNAs' (miRNAs) abnormal expression is one of the main factors of chemotherapy resistance in various cancers. However, the role of miRNAs in lung adenocarcinoma (LUAD) resistance to cisplatin is still unclear. In this study, we analyzed a microarray dataset to investigate miRNAs related to cisplatin resistance in LUAD. The expression of miRNAs in LUAD tissues and cell lines was detected using real-time quantitative polymerase chain reaction (RT-qPCR). Special AT-Rich Sequence-Binding Protein 2 (SATB2) in LUAD cell lines was detected using RT-qPCR and Western blot. Cell proliferation was measured by CCK8 and colony formation assays, while cell cycle and apoptosis were measured by flow cytometry. A dual-luciferase reporter assay was performed to confirm that SATB2 is a target gene of microRNA-660 (miR-660). We showed that the expression of miR-660 was not only decreased in LUAD cells and tissues but also further decreased in the cisplatin-resistant A549 cell line. The overexpression of miR-660 increased cisplatin sensitivity in LUAD cells. In addition, we identified SATB2 as a direct target gene of miR-660. We also revealed that miR-660 increased cisplatin sensitivity in LUAD cells via targeting SATB2. In conclusion, miR-660/SATB2 axis is a key regulator of cisplatin resistance in LUAD.

SATB1 Chromatin Loops Regulate Megakaryocyte/Erythroid Progenitor Expansion by Facilitating HSP70 and GATA1 Induction.

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations, and an increased risk of developing cancer. The chromatin-binding special AT-rich sequence-binding protein-1 (SATB1) is downregulated in megakaryocyte/erythroid progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors heat shock protein 70 (HSP70) and GATA1 which accompanies MEP differentiation. SATB1 binding to specific sites surrounding the HSP70 genes promotes chromatin loops that are required for the induction of HSP70, which, in turn, promotes GATA1 induction. This demonstrates that SATB1, although gradually downregulated during myelopoiesis, maintains a biological function in early myeloid progenitors.

Psammomatoid Ossifying Fibroma Is Defined by SATB2 Rearrangement.

Psammomatoid ossifying fibroma (PsOF), also known as juvenile PsOF, is a benign fibro-osseous neoplasm predominantly affecting the extragnathic bones, particularly the frontal and ethmoid bones, with a preference for adolescents and young adults. The clinical and morphologic features of PsOF may overlap with those of other fibro-osseous lesions, and additional molecular markers would help increase diagnostic accuracy. Because identical chromosomal breakpoints at bands Xq26 and 2q33 have been described in 3 cases of PsOF located in the orbita, we aimed to identify the exact genes involved in these chromosomal breakpoints and determine their frequency in PsOF using transcriptome sequencing and fluorescence in situ hybridization (FISH). We performed whole RNA transcriptome sequencing on frozen tissue in 2 PsOF index cases and identified a fusion transcript involving SATB2, located on chromosome 2q33.1, and AL513487.1, located on chromosome Xq26, in one of the cases. The fusion was validated using reverse transcription (RT)-PCR and SATB2 FISH. The fusion lead to a truncated protein product losing most of the functional domains. Subsequently, we analyzed an additional 24 juvenile PsOFs, 8 juvenile trabecular ossifying fibromas (JTOFs), and 11 cemento-ossifying fibromas (COFs) for SATB2 using FISH and found evidence of SATB2 gene rearrangements in 58% (7 of 12) of the evaluable PsOF cases but not in any of the evaluable JTOF (n = 7) and COF (n = 7) cases. A combination of SATB2 immunofluorescence and a 2-color SATB2 FISH in our index case revealed that most tumor cells harboring the rearrangement lacked SATB2 expression. Using immunohistochemistry, 65% of PsOF, 100% of JTOF, and 100% of COF cases showed moderate or strong staining for SATB2. In these cases, we observed a mosaic pattern of expression with >25% of the spindle cells in between the bone matrix, with osteoblasts and osteocytes being positive for SATB2. Interestingly, 35% (8 of 23) of PsOFs, in contrast to JTOFs and COFs, showed SATB2 expression in <5% of cells. To our knowledge, this is the first report that shows the involvement of SATB2 in the development of a neoplastic lesion. In this study, we have showed that SATB2 rearrangement is a recurrent molecular alteration that appears to be highly specific for PsOF. Our findings support that PsOF is not only morphologically and clinically but also genetically distinct from JTOF and COF.

SATB2, coordinated with CUX1, regulates IL-1ß-induced senescence-like phenotype in endothelial cells by fine-tuning the atherosclerosis-associated p16INK4a expression.

Genome-wide association studies (GWAS) have validated a strong association of atherosclerosis with the CDKN2A/B locus, a locus harboring three tumor suppressor genes: p14ARF , p15INK4b , and p16INK4a . Post-GWAS functional analysis reveals that CUX is a transcriptional activator of p16INK4a via its specific binding to a functional SNP (fSNP) rs1537371 on the atherosclerosis-associated CDKN2A/B locus, regulating endothelial senescence. In this work, we characterize SATB2, another transcription factor that specifically binds to rs1537371. We demonstrate that even though both CUX1 and SATB2 are the homeodomain transcription factors, unlike CUX1, SATB2 is a transcriptional suppressor of p16INK4a and overexpression of SATB2 competes with CUX1 for its binding to rs1537371, which inhibits p16INK4a and p16INK4a -dependent cellular senescence in human endothelial cells (ECs). Surprisingly, we discovered that SATB2 expression is transcriptionally repressed by CUX1. Therefore, upregulation of CUX1 inhibits SATB2 expression, which enhances the binding of CUX1 to rs1537371 and subsequently fine-tunes p16INK4a expression. Remarkably, we also demonstrate that IL-1ß, a senescence-associated secretory phenotype (SASP) gene itself and a biomarker for atherosclerosis, induces cellular senescence also by upregulating CUX1 and/or downregulating SATB2 in human ECs. A model is proposed to reconcile our findings showing how both primary and secondary senescence are activated via the atherosclerosis-associated p16INK4a expression.

SAFB2 Inhibits the Progression of Breast Cancer by Suppressing the Wnt/ß-Catenin Signaling Pathway via NFAT5.

Aberrant scaffold attachment factor-B2 (SAFB2) expression is associated with several malignant tumors. In this study, we investigated how SAFB2 worked in the process of breast cancer as well as the underlying mechanism. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis were used to investigate the expression of SAFB2 and nuclear factor of activated T cells 5 (NFAT5). Cellular proliferative ability was detected with cell counting kit 8 (CCK8), colony formation and 5-Ethynyl-2'-deoxyuridine (EdU) staining assays. Cell apoptosis was measured via flow cytometry and western blotting analysis. Wound healing, transwell assays, and western blotting analysis were executed to estimate cell migration and invasion. The relationship between SAFB2 and NFAT5 was verified by RNA immunoprecipitation (RIP) assay and NFAT5 mRNA stability was examined with actinomycin (Act) D assay. Western blotting analysis also tested the expression of Wnt/ß-catenin signaling-associated proteins. As a result, SAFB2 was downregulated in breast cancer cell lines, while NFAT5 was highly expressed in most breast cancer cell lines. Overexpression of SAFB2 suppressed the proliferation, migration, and invasion while exacerbated the apoptosis of breast cancer cells. SAFB2 interacted with NFAT5 mRNA and declined the stability of NFAT5 mRNA. Overexpression of NFAT5 counteracted anti-proliferative, anti-metastatic and pro-apoptotic effects of SAFB2 in breast cancer cells. Mechanistically, SAFB2 overexpression inhibited the Wnt/ß-catenin signaling pathway, while this effect was partially eliminated by NFAT5. Collectively, SAFB2 hindered breast cancer development and inactivated Wnt/ß-catenin signaling via regulation of NFAT5, suggesting that SAFB2 might be a promising therapeutic target for breast cancer.

YAP-Activated SATB2 Is a Coactivator of NRF2 That Amplifies Antioxidative Capacity and Promotes Tumor Progression in Renal Cell Carcinoma.

Aberrant epigenetic reprogramming contributes to the progression of renal cell carcinoma (RCC). Elucidation of key regulators of epigenetic reprogramming in RCC could help identify therapeutic vulnerabilities to improve treatment. Here, we report upregulation of the nuclear matrix-associated protein, special AT-rich binding protein-2 (SATB2), in RCC samples, which correlated with poor prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expression and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets to suppress oxidative stress without altering NRF2 levels. Integrated chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin using sequencing analyses demonstrated that SATB2 coordinated with NRF2 to drive enhancer-promoter interactions, amplifying transcriptional activity. SATB2 recruited SWI/SNF complex subunits, including BRD7 or BRG1, to sustain DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that rendered RCC more sensitive to SATB2 deficiency. Moreover, SATB2 ablation promoted the sensitivity of RCC to chemotherapy-induced apoptosis. Finally, targeting SATB2 or BRD7 effectively restricted the proliferation of YAP-high tumors in patient-derived xenografts and patient-derived organoids. Together, SATB2 is an oncogenic chromatin organizer in RCC, and targeting SATB2 is an effective strategy to suppress the YAP-high RCC. SIGNIFICANCE: A YAP-SATB2-NRF2 regulatory axis amplifies antioxidative stress signaling and provides potential therapeutic targets to enhance response to chemotherapy in renal cell carcinoma.

Special AT-rich sequence binding protein 1 promotes multidrug resistance in gastric cancer by regulation of Ezrin to alter subcellular localization of ATP-binding cassette transporters.

Multidrug resistance is a primary factor in the poor response to chemotherapy and subsequent death in gastric cancer patients. However, the molecular mechanisms involved remain unclear. In this study, the high expression of special AT-rich sequence binding protein 1 (SATB1) in gastric cancer was found to be associated with reduced sensitivity to various chemotherapy drugs. Our results demonstrate that SATB1 can promote chemotherapy resistance in gastric cancer in vitro and in vivo. SATB1 exerts its effect by enhancing the activity of multiple ATP-binding cassette (ABC) transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) in gastric cancer cell lines. We also found that SATB1 affects ABC transporters by altering the subcellular localization of the ABC transporter rather than its expression. Subsequently, we confirmed that Ezrin binds to various ABC transporters and affects their subcellular localization. In addition, we found that SATB1 can also bind to the Ezrin promoter and regulate its expression. In the present study, we elucidate the mechanism of SATB1-mediated multidrug resistance in gastric cancer, providing a basis for SATB1 as a potential target for reversal of resistance.

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.

HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.

IGFL2-AS1 facilitates tongue squamous cell carcinoma progression via Wnt/ß-catenin signaling pathway.

OBJECTIVES: Tongue squamous cell carcinoma (TSCC) is the most common malignancy in oral cancer. Long noncoding RNAs (lncRNAs) are important regulators in cancer biology. In our present study, we investigated a novel lncRNA IGF-like family member 2 antisense RNA 1 (IGFL2-AS1) in TSCC. METHODS: RT-qPCR analyzed IGFL2-AS1 expression in TSCC cells. Functional assays assessed the impact of IGFL2-AS1 on TSCC cell proliferation, migration, and invasion. Western blot analyzed the protein levels of EMT-related markers. Mechanism assays analyzed the regulatory mechanism of IGFL2-AS1 in TSCC cells. In-vivo experiments were conducted to prove the role of IGFL2-AS1 in TSCC progression. RESULTS: IGFL2-AS1 was significantly up-regulated in TSCC cells and tissues, and IGFL2-AS1 knockdown inhibited cell proliferation, migration, invasion and EMT in TSCC. Moreover, IGFL2-AS1 functioned as a competing endogenous RNA (ceRNA) to sponge miR-1224-5p and thereby modulated SATB homeobox 1 (SATB1) expression. Additionally, SATB1 activated the Wnt/ß-catenin signaling pathway in TSCC cells and IGFL2-AS1 regulated the Wnt/ß-catenin signaling pathway and TSCC progression via elevating SATB1 expression. CONCLUSIONS: The data revealed that IGFL2-AS1 played a cancer promoting role in TSCC and may aid in exploring a brand new biomarker that might contribute to TSCC treatment.

SATB1 promotes osteogenic differentiation of diabetic rat BMSCs through MAPK signalling activation.

OBJECTIVE: Special AT-rich binding protein 1 (SATB1), a chromatin organizer and global transcriptional regulator, plays an important role in tumorigenesis and immune response. However, its function in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) remains unknown. Therefore, this study aimed to explore the role of SATB1 in osteogenesis. METHODS: BMSCs were collected from the type 2 diabetes rat model and the protein and gene expression of SATB1 and osteospecific genes were evaluated post osteogenic induction. RESULTS: SATB1 protein expression significantly decreased in diabetic rat BMSCs whereas it increased in BMSCs following osteogenic induction. SATB1 knockdown significantly suppressed the expression of osteospecific genes, including alkaline phosphatase (Alp), runt-related transcription factor 2, and osteocalcin, and reduced the number of mineral deposits and ALP activity, whereas SATB1 overexpression yielded the opposite results. Moreover, SATB1 knockdown suppressed activation of the MAPK signalling pathway (phosphorylation of p38 and ERK), and MAPK pathway inhibitors could reverse the inhibitory effect of SATB1 knockdown on osteogenic differentiation of BMSCs. CONCLUSION: SATB1 plays a key role in the osteogenic differentiation of BMSCs via the p38 MAPK and ERK MAPK signalling pathways. These findings may provide a new strategy for the application of BMSCs in bone regeneration.