scholarly journals Epigenetic Regulation of miR-92a and TET2 and Their Association in Non-Hodgkin Lymphoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Esther K. Elliott ◽  
Lloyd N. Hopkins ◽  
Robert Hensen ◽  
Heidi G. Sutherland ◽  
Larisa M. Haupt ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Target Genes ◽  
Cpg Islands ◽  
Mature Mirnas ◽  
Tumour Suppressor Genes ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Non Hodgkin Lymphoma

MicroRNAs (miRNAs) are well known for their ability to regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. In various cancers, miRNAs regulate gene expression by altering the epigenetic status of candidate genes that are implicated in various difficult to treat haematological malignancies such as non-Hodgkin lymphoma by acting as either oncogenes or tumour suppressor genes. Cellular and circulating miRNA biomarkers could also be directly utilised as disease markers for diagnosis and monitoring of non-Hodgkin lymphoma (NHL); however, the role of DNA methylation in miRNA expression regulation in NHL requires further scientific inquiry. In this study, we investigated the methylation levels of CpGs in CpG islands spanning the promoter regions of the miR-17–92 cluster host gene and the TET2 gene and correlated them with the expression levels of TET2 mRNA and miR-92a-3p and miR-92a-5p mature miRNAs in NHL cell lines, tumour samples, and the whole blood gDNA of an NHL case control cohort. Increased expression of both miR-92a-3p and miR-92a-5p and aberrant expression of TET2 was observed in NHL cell lines and tumour tissues, as well as disparate levels of dysfunctional promoter CGI methylation. Both miR-92a and TET2 may play a concerted role in NHL malignancy and disease pathogenesis.

CAL-101 (GS-1101), a Specific Inhibitor of Phosphatidylinositol-3-Kinase-Delta (PI3Kδ), Disrupts Signals From the Microenvironment, Induces Apoptosis, and Enhances the Antitumor Activity of Everolimus (RAD001), An Inhibitor of Mammalian Target of Rapamycin (mTOR), in Mantle Cell Lymphoma (MCL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3730-3730 ◽  
Author(s):  
Sarah A Meadows ◽  
Adam Kashishian ◽  
David Johnson ◽  
Roger G Ulrich ◽  
Langdon L Miller ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Dependent Manner ◽  
Mtor Inhibition ◽  
Non Hodgkin Lymphoma

Abstract Abstract 3730 Background: The PI3K/Akt/mTOR pathway plays a critical role in cellular proliferation and survival through transduction of signals from cell-surface receptors to proteins involved in cell cycling (eg, cyclin D1) and mRNA translation (eg, ribosomal protein S6 and translation initiation factor 4E-binding protein 1 [4E-BP1]). MCL is an aggressive B-cell non-Hodgkin lymphoma. Overexpression of cyclin D1 has prompted clinical evaluation of mTOR inhibitors (everolimus, temsirolimus) in MCL. While efficacy has been observed, the extent and duration of tumor control has been modest, encouraging assessment of additional methods of intervention. Among the several PI3K isoforms (p110α, β, δ, γ), we have previously shown a unique role for PI3Kδ in maintaining the survival of hematological cancers and have also shown that GS-1101, a highly selective oral PI3Kδ-isoform-specific inhibitor with no activity against mTOR, shows promising clinical activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). These considerations prompted us to assess the specific role of PI3Kδ in MCL and to determine if dual PI3Kδ/mTOR inhibition might enhance antitumor effects. Results: In all evaluated MCL cell lines (Jeko, Mino, Granta, and NCEB), PI3Kδ levels were high while expression of PI3Kα, β, and γ were variable. PI3Kδ was functionally active, inducing phosphorylation of Akt (pAkt) in all tested cell lines and also in 4 of 4 primary MCL samples. Single-agent GS-1101 decreased pAkt in cell lines and primary samples. The pAkt decrease was associated with growth suppression and induction of apoptosis in all MCL cell lines. Consistent with these effects, immunoblotting showed that GS-1101 decreased cyclin D1 levels in MCL cell lines. Because signals from the tumor microenvironment are essential for homing, survival, and proliferation of malignant B cells, we investigated the potential role of PI3Kδ in mediating these signals by stimulating MCL lines with CXCL12 (SDF-1), CXCL13 (BCA-1), BAFF, or BCR crosslinking in the presence or absence of GS-1101. These stimuli all resulted in the phosphorylation of Akt, which was inhibited by GS-1101 in a dose-dependent manner. Furthermore, selective inhibition of PI3Kd was able to attenuate the upregulation of Akt phosphorylation and the secreation of CCL17 and CCL22 associated with coculturing MCL cells and stromal cells. Treatment with GS-1101 also decreased S6 phosphorylation, but levels of phospho-4E-BP1 remained high, suggesting that mTOR signaling was not completely inhibited. However, the combination of GS-1101 and everolimus suppressed phosphorylation of both S6 and 4E-BP1, inhibiting MCL viability and enhancing apoptosis relative to treatment with either GS-1101 or everolimus alone. Conclusions: Our findings indicate that excessive PI3Kδ activity is characteristic in MCL and GS-1101-mediated PI3Kδ inhibition reduces MCL growth and survival. Combination therapy to address the molecular complexity associated with the convergence of the PI3Kδ-Akt and mTOR pathways may provide a novel treatment approach for MCL. Disclosures: Meadows: Gilead Sciences: Employment. Kashishian:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment. Ulrich:Gilead Sciences: Employment. Miller:Gilead Sciences: Employment. Lannutti:Gilead Sciences: Employment.

Elevated NF-κB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4287-4293 ◽  
Author(s):  
Stephan Mathas ◽  
Korinna Jöhrens ◽  
Stefan Joos ◽  
Andreas Lietz ◽  
Franziska Hummel ◽  
...  
Keyword(s):  
T Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Target Genes ◽  
Large Cell ◽  
Non Hodgkin Lymphoma ◽  
T Cell Lymphomas ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Copy Number Increase

Transcription factor nuclear factor kappa B (NF-κB) plays a central role in the pathogenesis of classical Hodgkin lymphoma (cHL). In anaplastic large-cell lymphomas (ALCLs), which share molecular lesions with cHL, the NF-κB system has not been equivalently investigated. Here we describe constitutive NF-κB p50 homodimer [(p50)2] activity in ALCL cells in the absence of constitutive activation of the IκB kinase (IKK) complex. Furthermore, (p50)2 contributes to the NF-κB activity in Hodgkin/Reed-Sternberg (HRS) cells. Bcl-3, which is an inducer of nuclear (p50)2 and is associated with (p50)2 in ALCL and HRS cell lines, is abundantly expressed in ALCL and HRS cells. Notably, a selective overexpression of Bcl-3 target genes is found in ALCL cells. By immunohistochemical screening of 288 lymphoma cases, a strong Bcl-3 expression in cHL and in peripheral T-cell non-Hodgkin lymphoma (T-NHL) including ALCL was found. In 3 of 6 HRS cell lines and 25% of primary ALCL, a copy number increase of the BCL3 gene locus was identified. Together, these data suggest that elevated Bcl-3 expression has an important function in cHL and peripheral T-NHL, in particular ALCL.

DNA methylation events in transcription factors and gene expression changes in colon cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1593-1610
Author(s):  
Anna Díez-Villanueva ◽  
Rebeca Sanz-Pamplona ◽  
Robert Carreras-Torres ◽  
Ferran Moratalla-Navarro ◽  
M Henar Alonso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Colon Cancer ◽  
Transcription Factors ◽  
Target Genes ◽  
Linear Models ◽  
Cpg Islands ◽  
Promoter Regions ◽  
Differential Gene

Aim: Gain insight about the role of DNA methylation in the malignant growth of colon cancer. Patients & methods: Methylation and gene expression from 90 adjacent-tumor paired tissues and 48 healthy tissues were analyzed. Tumor genes whose change in expression was explained by changes in methylation were identified using linear models adjusted for tumor stromal content. Results: No differences in methylation were found between adjacent and healthy tissues, but clear differences were found between adjacent and tumor samples. We identified hypermethylated CpG islands located in promoter regions that drive differential gene expression of transcription factors and their target genes. Conclusion: Changes in methylation of a few genes provoke important changes in gene expression, by expanding the signal through transcription activation/repression.

scholarly journals Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3131
Author(s):  
Julia Paczkowska ◽  
Joanna Janiszewska ◽  
Adam Ustaszewski ◽  
Julia Bein ◽  
Marcin Skalski ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Target Genes ◽  
Cell Phenotype ◽  
Classical Hodgkin Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Hodgkin Lymphoma Cell ◽  
Mirna Expression Profiling

A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.

Methylation profiles of tumour suppressor genes in Hodgkin and non-Hodgkin lymphoma cell lines

2008 ◽  
Vol 2008 (Spring) ◽  
Author(s):  
Sonja Röhrs ◽  
Julia Romani ◽  
Wilhelm Dirks ◽  
Hans G. Drexler ◽  
Hilmar Quentmeier
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Tumour Suppressor ◽  
Lymphoma Cell ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
Non Hodgkin Lymphoma ◽  
Hodgkin Lymphoma Cell

scholarly journals EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yiming He ◽  
Mingxi Gan ◽  
Yanan Wang ◽  
Tong Huang ◽  
Jianbin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Potential Role ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Phosphorylation Site ◽  
Promoter Regions ◽  
Cycle Progression

AbstractGrainyhead-like 1 (GRHL1) is a transcription factor involved in embryonic development. However, little is known about the biological functions of GRHL1 in cancer. In this study, we found that GRHL1 was upregulated in non-small cell lung cancer (NSCLC) and correlated with poor survival of patients. GRHL1 overexpression promoted the proliferation of NSCLC cells and knocking down GRHL1 inhibited the proliferation. RNA sequencing showed that a series of cell cycle-related genes were altered when knocking down GRHL1. We further demonstrated that GRHL1 could regulate the expression of cell cycle-related genes by binding to the promoter regions and increasing the transcription of the target genes. Besides, we also found that EGF stimulation could activate GRHL1 and promoted its nuclear translocation. We identified the key phosphorylation site at Ser76 on GRHL1 that is regulated by the EGFR-ERK axis. Taken together, these findings elucidate a new function of GRHL1 on regulating the cell cycle progression and point out the potential role of GRHL1 as a drug target in NSCLC.

scholarly journals Histone Modifying Enzymes in Gynaecological Cancers

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 816
Author(s):  
Priya Ramarao-Milne ◽  
Olga Kondrashova ◽  
Sinead Barry ◽  
John D. Hooper ◽  
Jason S. Lee ◽  
...  
Keyword(s):  
Genome Instability ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Driver Mutations ◽  
Promoter Regions ◽  
Post Translational Modifications ◽  
Chromatin Dynamics ◽  
Cancer Types ◽  
Histone Modifying Enzymes

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.

P04.20 The role of YAP in Glioblastoma cell lines

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii22-ii23
Author(s):  
G Casati ◽  
L Giunti ◽  
A Iorio ◽  
A Marturano ◽  
I Sardi
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Western Blotting ◽  
Cytotoxic Effect ◽  
Target Genes ◽  
Hippo Pathway ◽  
Combined Treatment ◽  
Set Up ◽  
The Hippo Pathway

Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.

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