scholarly journals Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo

2020 ◽  
Vol 6 (21) ◽  
pp. eaay3823 ◽  
Author(s):  
Aniek van der Vaart ◽  
Molly Godfrey ◽  
Vincent Portegijs ◽  
Sander van den Heuvel
Keyword(s):  
Cell Proliferation ◽  
Human Cancer ◽  
Gene Knockout ◽  
Polycomb Group ◽  
Regulatory Function ◽  
Specific Gene ◽  
Suppressor Activity ◽  
Protein Levels ◽  
Genes Encoding

SWI/SNF (switch/sucrose nonfermenting) complexes regulate transcription through chromatin remodeling and opposing gene silencing by Polycomb group (PcG) proteins. Genes encoding SWI/SNF components are critical for normal development and frequently mutated in human cancer. We characterized the in vivo contributions of SWI/SNF and PcG complexes to proliferation-differentiation decisions, making use of the reproducible development of the nematode Caenorhabditis elegans. RNA interference, lineage-specific gene knockout, and targeted degradation of SWI/SNF BAF components induced either overproliferation or acute proliferation arrest of precursor cells, depending on residual protein levels. Our data show that a high SWI/SNF BAF dosage is needed to arrest cell division during differentiation and to oppose PcG-mediated repression. In contrast, a low SWI/SNF protein level is necessary to sustain cell proliferation and hyperplasia, even when PcG repression is blocked. These observations show that incomplete inactivation of SWI/SNF components can eliminate a tumor-suppressor activity while maintaining an essential transcription regulatory function.

scholarly journals Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo

2019 ◽  
Author(s):  
Aniek van der Vaart ◽  
Molly Godfrey ◽  
Vincent Portegijs ◽  
Sander van den Heuvel
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Repression ◽  
Human Cancer ◽  
Gene Knockout ◽  
Selective Advantage ◽  
Polycomb Group ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Suppressor Activity

AbstractSWI/SNF complexes regulate transcription through chromatin remodeling and opposing gene silencing by Polycomb-group (PcG) proteins. Genes that encode SWI/SNF subunits are frequently mutated in human cancer. The selective advantage, subunit bias, and common heterozygosity of such mutations remains poorly understood. Here, we characterized how functional loss of various SWI/SNF subunits and PcG EZH2 affect proliferation-differentiation decisions in vivo, making use of the reproducible development of the nematode C. elegans. We applied a lineage-specific genetics strategy to create partial or complete SWI/SNF subunit loss, as well as double gene knockout with PcG EZH2. Our data show that a high SWI/SNF BAF dosage is needed to oppose Polycomb-mediated transcriptional repression and to arrest cell division during differentiation. In contrast, even in the absence of the PcG EZH2-related methyltransferase, a low level of the SWI/SNF BAF complex is necessary and sufficient to sustain cell proliferation and hyperplasia. Our data provide experimental support for the theory that during carcinogenesis partial SWI/SNF BAF loss-of-function mutations are selected because they eliminate a tumor suppressor activity while maintaining an essential transcription regulatory function.

scholarly journals Knockdown of circRNA_0007534 suppresses the tumorigenesis of cervical cancer via miR-206/GREM1 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qiang Sun ◽  
Xiangying Qi ◽  
Wenyan Zhang ◽  
Xiaoyu Li
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Regulatory Function ◽  
Circular Rnas ◽  
Protein Levels ◽  
Novel Mirna ◽  
The Impact

Abstract Background Increasing evidence manifested that circular RNAs (circRNAs) acted as crucial regulators in human cancers by targeting the miRNA/mRNA axis, including cervical cancer (CC). Circ_0007534 was reported to promote CC cell proliferation and invasion by the miR-498/BMI-1 axis. The aim of this study was to explore a novel miRNA/mRNA network underlying circ_0007534 in CC regulation. Methods The quantitative real-time polymerase chain reaction (qRT-PCR) was implemented to examine the levels of circ_0007534, miR-206 and Gremlin1 (GREM1). Cell viability was determined using MTT assay. BrdU and colony formation assays were performed for analyzing cell proliferation. Cell apoptosis was assessed by flow cytometry. The protein levels of GREM1 and apoptotic markers (Bcl-2, Bax, C-Caspase3) were measured via western blot. Cell invasion was detected by transwell assay. The target relationship was analyzed by dual-luciferase reporter assay. The impact of circ_0007534 on CC growth in vivo was ascertained by xenograft assay. Results Circ_0007534 expression was aberrantly increased in CC tissues and cells. Functionally, knockdown of circ_0007534 reduced CC cell growth and invasion but motivated apoptosis. In the mechanism, circ_0007534 targeted miR-206 and its regulatory function was associated with sponging miR-206. Moreover, circ_0007534 was found to regulate GREM1 level by targeting miR-206. The inhibitory effect of si-circ_0007534 on the malignant progression of CC was reversed after GREM1 was overexpressed. Furthermore, circ_0007534 inhibition also reduced tumor growth of CC in vivo partially by regulating miR-206/GREM1 axis. Conclusion These results suggested that knockdown of circ_0007534 promoted the level of miR-206 to induce the expression downregulation of GREM1, consequently inhibiting the progression of CC.

scholarly journals Long non-coding RNA CCDC183-AS1 acts AS a miR-589-5p sponge to promote the progression of hepatocellular carcinoma through regulating SKP1 expression

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
He Zhu ◽  
Hongwei Zhang ◽  
Youliang Pei ◽  
Zhibin Liao ◽  
Furong Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Human Cancer ◽  
Quantitative Polymerase Chain Reaction ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
High Morbidity ◽  
Regulatory Relationship

Abstract Background Hepatocellular carcinoma (HCC) is a common type of malignant human cancer with high morbidity and poor prognosis, causing numerous deaths per year worldwide. Growing evidence has been demonstrated that long non-coding RNAs (lncRNAs) are closely associated with hepatocarcinogenesis and metastasis. However, the roles, functions, and working mechanisms of most lncRNAs in HCC remain poorly defined. Methods Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression level of CCDC183-AS1 in HCC tissues and cell lines. Cell proliferation, migration and invasion ability were evaluated by CCK-8 and transwell assay, respectively. Animal experiments were used to explore the role of CCDC183-AS1 and miR-589-5p in vivo. Bioinformatic analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the regulatory relationship between CCDC183-AS1, miR-589-5p and SKP1. Results Significantly upregulated expression of CCDC183-AS1 was observed in both HCC tissues and cell lines. HCC patients with higher expression of CCDC183-AS1 had a poorer overall survival rate. Functionally, overexpression of CCDC183-AS1 markedly promoted HCC cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas the downregulation of CCDC183-AS1 exerted opposite effects. MiR-589-5p inhibitor counteracted the proliferation, migration and invasion inhibitory effects induced by CCDC183-AS1 silencing. Mechanistically, CCDC183-AS1 acted as a ceRNA through sponging miR-589-5p to offset its inhibitory effect on the target gene SKP1, then promoted the tumorigenesis of HCC. Conclusions CCDC183-AS1 functions as an oncogene to promote HCC progression through the CCDC183-AS1/miR-589-5p/SKP1 axis. Our study provided a novel potential therapeutic target for HCC patients.

RUNX2 promotes malignant progression in gastric cancer by regulating COL1A1

2021 ◽  
pp. 1-12
Author(s):  
Yanlei Li ◽  
Ran Sun ◽  
Xiulan Zhao ◽  
Baocun Sun
Keyword(s):  
Gastric Cancer ◽  
Human Cancer ◽  
Clinical Stage ◽  
Collagen Type I ◽  
Migration And Invasion ◽  
Type I ◽  
Aberrant Expression ◽  
Invasion And Migration ◽  
Protein Levels

BACKGROUND: Runt-related transcription factor 2 (RUNX2) is an important gene that has been implicated in the progression of human cancer. Aberrant expression of RUNX2 predicts gastric cancer (GC) metastasis. However, the molecular mechanism of RUNX2 remains unknown. OBJECTIVE: We hypothesize that RUNX2 promotes GC metastasis by regulating the extracellular matrix component collagen type I alpha 1 (COL1A1). METHODS: The GEPIA database and immunohistochemical staining of 60 GC tissues were used to analyse the correlations between RUNX2 or COL1A1 expression and clinicopathological features, and the Kaplan-Meier method was used to evaluate survival. RT-PCR, western blotting and immunofluorescence were used to detect RUNX2 and COL1A1 expression in GC cells. Migration and invasion assays were performed to assess the influence of RUNX2 and COL1A1 on metastasis. RESULTS: RUNX2 and COL1A1 were highly expressed at both the gene and protein levels in GC, and patients who were positive for RUNX2 and COL1A1 had shorter survival. RUNX2 and COL1A1 expression linearly correlated with each other (r= 0.15, p< 0.01) and with clinical stage and lymph node metastasis (p< 0.05). Overexpressing RUNX2in vitro enhanced COL1A1 expression and promoted GC cell invasion and migration, whereas COL1A1 knockdown inhibited the increase in cell metastatic capacity promoted by RUNX2. In vivo, GC cells overexpressing RUNX2 promoted lung metastasis, and the downregulation of COL1A1 reduced the metastasis promoted by RUNX2. CONCLUSIONS: RUNX2 may promote GC metastasis by regulating COL1A1. RUNX2/COL1A1 can be employed as a novel target for therapy in GC.

scholarly journals Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

2018 ◽  
Vol 51 (1) ◽  
pp. 113-128 ◽  
Author(s):  
Jia Zhu ◽  
Rui Zhang ◽  
Dongxiang Yang ◽  
Jibin Li ◽  
Xiaofei Yan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Regulatory Function ◽  
Glutathione S Transferase ◽  
Protein Levels ◽  
Qrt Pcr ◽  
Ic50 Value

Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

scholarly journals CSNK2 in cancer: pathophysiology and translational applications

2021 ◽  
Author(s):  
Scott W. Strum ◽  
Laszlo Gyenis ◽  
David W. Litchfield
Keyword(s):  
Human Cancer ◽  
Cell Cycle Control ◽  
Prognostic Significance ◽  
Hematologic Malignancies ◽  
Protein Levels ◽  
Wide Range ◽  
Positive Treatment ◽  
Extensive Body

AbstractProtein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase frequently dysregulated in solid and hematologic malignancies. To consolidate a wide range of biological and clinically oriented data from this unique kinase in cancer, this systematic review summarises existing knowledge from in vitro, in vivo and pre-clinical studies on CSNK2 across 24 different human cancer types. CSNK2 mRNA transcripts, protein levels and activity were found to be routinely upregulated in cancer, and commonly identified phosphotargets included AKT, STAT3, RELA, PTEN and TP53. Phenotypically, it frequently influenced evasion of apoptosis, enhancement of proliferation, cell invasion/metastasis and cell cycle control. Clinically, it held prognostic significance across 14 different cancers, and its inhibition in xenograft experiments resulted in a positive treatment response in 12. In conjunction with commentary on preliminary studies of CSNK2 inhibitors in humans, this review harmonises an extensive body of CSNK2 data in cancer and reinforces its emergence as an attractive target for cancer therapy. Continuing to investigate CSNK2 will be crucial to advancing our understanding of CSNK2 biology, and offers the promise of important new discoveries scientifically and clinically.

scholarly journals Mouse models for BRAF-induced cancers

2007 ◽  
Vol 35 (5) ◽  
pp. 1329-1333 ◽  
Author(s):  
C. Pritchard ◽  
L. Carragher ◽  
V. Aldridge ◽  
S. Giblett ◽  
H. Jin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Models ◽  
Human Cancer ◽  
Cre Recombinase ◽  
Genetically Engineered ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Single Nucleotide Change

Oncogenic mutations in the BRAF gene are detected in ∼7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine→glutamate mutation at residue 600 (V600EBRAF). In cells cultured in vitro, V600EBRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that V600EBRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.

Effect and mechanism of YB-1 knockdown on glioma cell growth, migration, and apoptosis

2020 ◽  
Vol 52 (2) ◽  
pp. 168-179 ◽  
Author(s):  
Huilin Gong ◽  
Shan Gao ◽  
Chenghuan Yu ◽  
Meihe Li ◽  
Ping Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Glioma Cell ◽  
Cell Transformation ◽  
Malignant Cell ◽  
Protein Levels ◽  
Glioma Progression

Abstract Y-box binding protein 1 (YB-1) is manifested as its involvement in cell proliferation and differentiation and malignant cell transformation. Overexpression of YB-1 is associated with glioma progression and patient survival. The aim of this study is to investigate the influence of YB-1 knockdown on glioma cell progression and reveal the mechanisms of YB-1 knockdown on glioma cell growth, migration, and apoptosis. It was found that the knockdown of YB-1 decreased the mRNA and protein levels of YB-1 in U251 glioma cells. The knockdown of YB-1 significantly inhibited cell proliferation, colony formation, and migration in vitro and tumor growth in vivo. Proteome and phosphoproteome data revealed that YB-1 is involved in glioma progression through regulating the expression and phosphorylation of major proteins involved in cell cycle, adhesion, and apoptosis. The main regulated proteins included CCNB1, CCNDBP1, CDK2, CDK3, ADGRG1, CDH-2, MMP14, AIFM1, HO-1, and BAX. Furthermore, it was also found that YB-1 knockdown is associated with the hypo-phosphorylation of ErbB, mTOR, HIF-1, cGMP-PKG, and insulin signaling pathways, and proteoglycans in cancer. Our findings indicated that YB-1 plays a key role in glioma progression in multiple ways, including regulating the expression and phosphorylation of major proteins associated with cell cycle, adhesion, and apoptosis.

scholarly journals Actions and Potential Therapeutic Applications of Growth Hormone–Releasing Hormone Agonists

Endocrinology ◽  
2019 ◽  
Vol 160 (7) ◽  
pp. 1600-1612 ◽  
Author(s):  
Andrew V Schally ◽  
Xianyang Zhang ◽  
Renzhi Cai ◽  
Joshua M Hare ◽  
Riccarda Granata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cardiac Tissue ◽  
Human Cancer ◽  
Large Body ◽  
Neuroprotective Effects ◽  
Promote Cell Proliferation ◽  
Therapeutic Applications ◽  
Human Cancer Cells

Abstract In this article, we briefly review the identification of GHRH, provide an abridged overview of GHRH antagonists, and focus on studies with GHRH agonists. Potent GHRH agonists of JI and MR class were synthesized and evaluated biologically. Besides the induction of the release of pituitary GH, GHRH analogs promote cell proliferation and exert stimulatory effects on various tissues, which express GHRH receptors (GHRH-Rs). A large body of work shows that GHRH agonists, such as MR-409, improve pancreatic β-cell proliferation and metabolic functions and facilitate engraftment of islets after transplantation in rodents. Accordingly, GHRH agonists offer a new therapeutic approach to treating diabetes. Various studies demonstrate that GHRH agonists promote repair of cardiac tissue, producing improvement of ejection fraction and reduction of infarct size in rats, reduction of infarct scar in swine, and attenuation of cardiac hypertrophy in mice, suggesting clinical applications. The presence of GHRH-Rs in ocular tissues and neuroprotective effects of GHRH analogs in experimental diabetic retinopathy indicates their possible therapeutic applications for eye diseases. Other effects of GHRH agonists, include acceleration of wound healing, activation of immune cells, and action on the central nervous system. As GHRH might function as a growth factor, we examined effects of GHRH agonists on tumors. In vitro, GHRH agonists stimulate growth of human cancer cells and upregulate GHRH-Rs. However, in vivo, GHRH agonists inhibit growth of human cancers xenografted into nude mice and downregulate pituitary and tumoral GHRH-Rs. Therapeutic applications of GHRH analogs are discussed. The development of GHRH analogs should lead to their clinical use.

scholarly journals Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-κB–dependent DNA methyltransferase activity in acute myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2364-2373 ◽  
Author(s):  
Shujun Liu ◽  
Zhongfa Liu ◽  
Zhiliang Xie ◽  
Jiuxia Pang ◽  
Jianhua Yu ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Zinc Finger Protein ◽  
Human Cancer ◽  
Proteasomal Degradation ◽  
Physical Interaction ◽  
Dna Hypomethylation ◽  
Methyltransferase Activity ◽  
Protein Levels

Bortezomib reversibly inhibits 26S proteasomal degradation, interferes with NF-κB, and exhibits antitumor activity in human malignancies. Zinc finger protein Sp1 transactivates DNMT1 gene in mice and is functionally regulated through protein abundance, posttranslational modifications (ie, ubiquitination), or interaction with other transcription factors (ie, NF-κB). We hypothesize that inhibition of proteasomal degradation and Sp1/NF-κB–mediated transactivation may impair aberrant DNA methyltransferase activity. We show here that, in addition to inducing accumulation of polyubiquitinated proteins and abolishment of NF-κB activities, bortezomib decreases Sp1 protein levels, disrupts the physical interaction of Sp1/NF-κB, and prevents binding of the Sp1/NF-κB complex to the DNMT1 gene promoter. Abrogation of Sp1/NF-κB complex by bortezomib causes transcriptional repression of DNMT1 gene and down-regulation of DNMT1 protein, which in turn induces global DNA hypomethylation in vitro and in vivo and re-expression of epigenetically silenced genes in human cancer cells. The involvement of Sp1/NF-κB in DNMT1 regulation is further demonstrated by the observation that Sp1 knockdown using mithramycin A or shRNA decreases DNMT1 protein levels, which instead are increased by Sp1 or NF-κB overexpression. Our results unveil the Sp1/NF-κB pathway as a modulator of DNA methyltransferase activity in human cancer and identify bortezomib as a novel epigenetic-targeting drug.

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