Epigenetic downregulation of STAT6 increases HIF-1α expression via mTOR/S6K/S6, leading to enhanced hypoxic viability of glioma cells

Park, Soo Jung; Kim, Hyunmi; Kim, Se Hyuk; Joe, Eun‐Hye; Jou, Ilo

doi:10.1186/s40478-019-0798-z

Cited by 18 publications

(9 citation statements)

References 54 publications

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“…Cytokines IL-4 and IL-13. And also interacted with and immune cells (B and T cells, macrophages, dendritic cells, and innate lymphoid cells in brain tumors [17] . STAT6 signaling inactivation can occur via ubiquitination and proteasomal degradation, facilitating cancer cell survival in a hypoxic microenvironment [18] .…”

Section: Discussionmentioning

confidence: 99%

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Expression of transcription factors (STAT 2, 3, 4, and 6, HDAC1, HDAC2) in craniopharyngioma

2021

AJOHC

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Background: Craniopharyngioma is a benign tumor of the sellar region that is typically characterized by a maldevelopment tumor with a high recurrence rate, as well as substantial morbidity and mortality in the long term. Signal transducers and transcription activators have been identified as critical components of cytokine signaling pathways that have previously been documented in craniopharyngioma-related literature. Purpose: The primary goal of this investigation is to examine transcription factor expression in craniopharyngiomas. In addition, a clinical-pathological and immunohistochemistry correlation will be sought. The current study enlisted the participation of forty patients. AdaCPs exhibited: β-catenin STAT2, STAT3, STAT6, and HDAC1 expression. While, STAT4, HDAC2, and GATA 3 were all negative. TTF1 was found in proteinaceous substances within the cyst formation (OMF). β-FGR, DPGR, TNFa, and Nrf2 were found to be associated with inflammation, OMF presence, and finger protrusion in brain surrounding tissue or brain invasion. Conclusions: Tumor recurrence was associated with increased expression of STAT3, STAT6, HDAC, β-catenin, and TNFα in WLA when compared to no recurrence. Coexpression of β-catenin, STAT2, STAT3, and STAT6 with TNFα was also shown using double fluorescence merge stains. There was no association between HDAC1 and HDAC2 coexpression and β-catenin, notably in the WLAs. Discussion: Histologically complicated features include cystic and solid components, the latter of which is made up of diverse morphological cell types. HDAC1 and HDAC2 regulate the enhanced expression of inflammatory genes during inflammation and macrophage response.

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Section: Discussionmentioning

confidence: 99%

“…STAT6 signaling inactivation can occur via ubiquitination and proteasomal degradation, facilitating cancer cell survival in a hypoxic microenvironment [18] . STAT6 increases HIF-1α expression via mTOR/S6K/S6 [17,19] . Expression of stat6 in Cps is correlated to tumor invasion and recurrent tumors.…”

Section: Discussionmentioning

confidence: 99%

Expression of transcription factors (STAT 2, 3, 4, and 6, HDAC1, HDAC2) in craniopharyngioma

2021

AJOHC

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“…Additionally, STAT6 is an important target protein of IL-4 that likely regulates the microenvironment of tumor cell growth, inhibits tumor invasion, and reduces tumor proliferation and differentiation (Rahaman et al, 2005 ; Hammond et al, 2018 ). Both in human glioma tissue and glioblastoma cells (U87MG and U373MG), Park et al ( 2019 ) found that CpG islands in the STAT6 promoter were hypermethylated by DNA methyltransferase which ultimately led to the down-regulated and even silenced expression of STAT6. Furthermore, under hypoxic conditions, the decrease of STAT6 could activate the mTOR signaling pathway, promote hypoxia-inducible factor-1 (HIF-1α) protein synthesis, and eventually enhance the viability and anti-apoptotic ability of tumor cells.…”

Section: Il-4 Glial Cells and Epilepsymentioning

confidence: 99%

“…Furthermore, under hypoxic conditions, the decrease of STAT6 could activate the mTOR signaling pathway, promote hypoxia-inducible factor-1 (HIF-1α) protein synthesis, and eventually enhance the viability and anti-apoptotic ability of tumor cells. Using DNA methyltransferase inhibitors, such as five-azacitidine and decitabine, to restore STAT6 expression in STAT6-silenced gliomas can increase tumor cell death, which would provide a new treatment (Park et al, 2019 ). Interestingly, in glioblastoma cells (U251, T98G, and A172), Rahaman et al found that IL-4 induced the abnormal activation of STAT3 in GBM cells, but not in normal human astrocytes.…”

Section: Il-4 Glial Cells and Epilepsymentioning

confidence: 99%

Interleukin 4 Affects Epilepsy by Regulating Glial Cells: Potential and Possible Mechanism

Chen

Zhu

Lü

et al. 2020

Front. Mol. Neurosci.

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Epilepsy is a chronic brain dysfunction induced by an abnormal neuronal discharge that is caused by complicated psychopathologies. Recently, accumulating studies have revealed a close relationship between inflammation and epilepsy. Specifically, microglia and astrocytes are important inflammatory cells in the central nervous system (CNS) that have been proven to be related to the pathogenesis and development of epilepsy. Additionally, interleukin 4 (IL-4) is an anti-inflammatory factor that can regulate microglia and astrocytes in many aspects. This review article focuses on the regulatory role of IL-4 in the pathological changes of glial cells related to epilepsy. We additionally propose that IL-4 may play a protective role in epileptogenesis and suggest that IL-4 may be a novel therapeutic target for the treatment of epilepsy.

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“…These cancer cell lines have acquired mutations and aberrant epigenetic marks that enable them to display malignancy. For example, the LN229 cell line was found to have mutations in p53 (Van Meir et al, 1994), deletions of p16 and p18 tumour suppressor genes (Wiedemeyer et al, 2008), and DNA methylations that epigenetically silence expression of tumour suppressor STAT6 (Park et al, 2019). There are other more somatic mutations and epigenetic alterations in these cell lines that will not be described here.…”

Section: Acly Overexpression Has No Role In Inducing Permanent Histone Acetylations To Regulate Expression Of Dna Damage Response Proteinmentioning

confidence: 99%

Contribution of metabolic alterations to genome instability and its association with cancer development

Woo¹

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Contribution of metabolic alterations to genome instability and its association with cancer development Woo Ren He SCHOOL OF BIOLOGICAL SCIENCESA thesis submitted to the Nanyang Technological University in partial fulfilment of the requirement for the degree of Doctor of Philosophy 2021 1.7.3. Determine if ACLY overexpression elevated ROS production to induce oxidative DNA damage vi-(ii) 1.7.4. Determine if ACLY overexpression led to the deregulation of ATR and ATM-mediated DNA damage responses 1.7.5. Determine if ACLY overexpression deregulated proteins involved in cell cycle checkpoint arrest, DNA damage repair, and apoptosis 1.7.6. Determining presence of global histone acetylations in ACLY-overexpressing cells 1.7.7. Determine if the effects of ACLY overexpression in the cell enabled the acquisition of cancer phenotypes 1.8. Significance of study 2. Methods 2.1. Cell lines and maintenance 2.1.1. The consideration on the use of cell lines that best represents normal cell phenotype 2.1.2. Culturing conditions of cell lines 2.2. Generating pXJ40-FLAG-ACLY vector and transfection 2.2.1. Generating pXJ40-FLAG-ACLY vector 2.2.2. Lipofectamine™2000-based transfection of pXJ40-FLAG-ACLY and pXJ40-FLAG vectors 2.3. Generation and maintenance of stable cell lines for doxycycline-inducible expression of ACLY 2.3.1. Generating pSLIK-Neo-TRE-FLAG-ACLY expression vector 2.3.2. Lentiviral production 2.3.3. Determining titer of lentiviral stocks 2.3.4. Lentiviral transduction to generate stable HME1-ACLY and HME1-Empty cells 2.4. Immunofluorescent staining 2.4.1. Cell fixation, permeabilisation, and immunostaining conditions 2.4.2. Studies on transfected hTERT-HME1 and hTERT-RPE1 cells 2.4.3. Studies on stable HME1-ACLY and HME1-Empty cell lines 2.5. Acid histone extraction 2.6. Western Blotting and Coomassie blue staining 2.6.1. Protein extraction, sample preparation, and SDS-PAGE vi-(iii) 2.6.2. Western blotting 2.6.3. Coomassie blue staining 2.6.4. Studies on transfected hTERT-HME1 and hTERT-RPE1 cells 2.6.5. Studies on stable HME1-ACLY and HME1-Empty cell lines 2.7. Flow cytometry analysis 2.7.1. DNA staining 2.7.2. Intracellular staining 2.7.3. Studies on stable HME1-ACLY and HME1-Empty cell lines 2.8. Neutral comet assay 2.9. Detecting levels of reactive oxygen species in live cells 2.10. MTT cell proliferation assay 2.11. TUNEL assay 2.12. Soft agar colony formation assay 2.13. Biosafety, chemical safety, and workplace safety 2.13.1. Safe handling of biological agents 2.13.2. Safe handling of hazardous and flammable chemicals 2.13.3. Workplace safety 3. Results 3.1. Nuclear abnormalities in a form of micronuclei structures were observed in cells that were ectopically expressing ACLY 3.2. HME1-ACLY stable cells were verified to overexpress ACLY upon doxycycline induction 3.3. Nuclear abnormalities associated with genome instability were caused by DNA damage 3.3.1 Increased population of cells with micronuclei and nuclear budding structures were observed 3.3.2 The CBMN assay revealed an increased population of binuclear...

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Epigenetic downregulation of STAT6 increases HIF-1α expression via mTOR/S6K/S6, leading to enhanced hypoxic viability of glioma cells

Cited by 18 publications

References 54 publications

Expression of transcription factors (STAT 2, 3, 4, and 6, HDAC1, HDAC2) in craniopharyngioma

Expression of transcription factors (STAT 2, 3, 4, and 6, HDAC1, HDAC2) in craniopharyngioma

Interleukin 4 Affects Epilepsy by Regulating Glial Cells: Potential and Possible Mechanism

Contribution of metabolic alterations to genome instability and its association with cancer development

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