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1.
Sci Rep ; 13(1): 19885, 2023 11 14.
Article in English | MEDLINE | ID: mdl-37963940

ABSTRACT

The dosage-dependent recruitment of RNA polymerase II (Pol II) at the promoters of genes related to neurodevelopment and stem cell maintenance is required for transcription by the fine-tuned expression of SET-domain-containing protein 5 (SETD5). Pol II O-GlcNAcylation by O-GlcNAc transferase (OGT) is critical for preinitiation complex formation and transcription cycling. SETD5 dysregulation has been linked to stem cell-like properties in some cancer types; however, the role of SETD5 in cancer cell stemness has not yet been determined. We here show that aberrant SETD5 overexpression induces stemness in colorectal cancer (CRC) cells. SETD5 overexpression causes the upregulation of PI3K-AKT pathway-related genes and cancer stem cell (CSC) markers such as CD133, Kruppel-like factor 4 (KLF4), and estrogen-related receptor beta (ESRRB), leading to the gain of stem cell-like phenotypes. Our findings also revealed a functional relationship between SETD5, OGT, and Pol II. OGT-catalyzed Pol II glycosylation depends on SETD5, and the SETD5-Pol II interaction weakens in OGT-depleted cells, suggesting a SETD5-OGT-Pol II interdependence. SETD5 deficiency reduces Pol II occupancy at PI3K-AKT pathway-related genes and CD133 promoters, suggesting a role for SETD5-mediated Pol II recruitment in gene regulation. Moreover, the SETD5 depletion nullified the SETD5-induced stemness of CRC cells and Pol II O-GlcNAcylation. These findings support the hypothesis that SETD5 mediates OGT-catalyzed O-GlcNAcylation of RNA Pol II, which is involved in cancer cell stemness gain via CSC marker gene upregulation.


Subject(s)
Colorectal Neoplasms , RNA Polymerase II , Humans , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , N-Acetylglucosaminyltransferases/metabolism , Colorectal Neoplasms/genetics , Catalysis , Protein Processing, Post-Translational , Methyltransferases/metabolism
2.
Int J Mol Sci ; 23(14)2022 Jul 11.
Article in English | MEDLINE | ID: mdl-35887001

ABSTRACT

JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04.


Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Cell Cycle Checkpoints , Histone Demethylases , Jumonji Domain-Containing Histone Demethylases , Liver Neoplasms , Aminopyridines , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/physiology , Cell Line, Tumor , Histone Demethylases/antagonists & inhibitors , Histone Demethylases/metabolism , Histone Demethylases/pharmacology , Histones/metabolism , Humans , Hydrazones , Jumonji Domain-Containing Histone Demethylases/pharmacology , Jumonji Domain-Containing Histone Demethylases/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Lysine/metabolism , Neoplasm Recurrence, Local/metabolism , Neoplastic Stem Cells/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism
3.
Cell Death Differ ; 27(12): 3273-3288, 2020 12.
Article in English | MEDLINE | ID: mdl-32555450

ABSTRACT

Brpf-histone acetyltransferase (HAT) complexes have important roles in embryonic development and regulating differentiation in ESCs. Among Brpf family, Brpf3 is a scaffold protein of Myst2 histone acetyltransferase complex that plays crucial roles in gene regulation, DNA replication, development as well as maintaining pluripotency in embryonic stem cells (ESCs). However, its biological functions in ESCs are not elucidated. In this study, we find out that Brpf3 protein level is critical for Myst2 stability and E3 ligase Huwe1 functions as a novel negative regulator of Myst2 via ubiquitin-mediated degradation. Importantly, Brpf3 plays an antagonistic role in Huwe1-mediated degradation of Myst2, suggesting that protein-protein interaction between Brpf3 and Myst2 is required for retaining Myst2 stability. Further, Brpf3 overexpression causes the aberrant upregulation of Myst2 protein levels which in turn induces the dysregulated cell-cycle progression and also delay of early embryonic development processes such as embryoid-body formation and lineage commitment of mouse ESCs. The Brpf3 overexpression-induced phenotypes can be reverted by Huwe1 overexpression. Together, these results may provide novel insights into understanding the functions of Brpf3 in proper differentiation as well as cell-cycle progression of ESCs via regulation of Myst2 stability by obstructing Huwe1-mediated ubiquitination. In addition, we suggest that this is a useful report which sheds light on the function of an unknown gene in ESC field.


Subject(s)
Embryonic Stem Cells/cytology , Gene Expression Regulation , Histone Acetyltransferases/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Cell Differentiation , Cell Division , Histone Acetyltransferases/genetics , Mice , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Ubiquitination
4.
Mindfulness (N Y) ; 10(7): 1255-1268, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31537988

ABSTRACT

OBJECTIVE: A significant subset of college students experience PTSD symptoms, and many engage in problematic alcohol use. Some college students with PTSD symptoms may use alcohol and other substances to cope with their symptoms, and those with PTSD experience more negative alcohol and drug consequences than those without PTSD. Mindfulness-Based Interventions (MBIs) have been successfully utilized for individuals with PTSD or substance use disorders. However, to date, no studies have evaluated MBIs for college students with co-occurring PTSD symptoms and problem drinking. METHOD: This study was a feasibility pilot of a 4-week group loving-kindness meditation (LKM) intervention, a practice of intentionally directing well wishes to oneself and others. LKM was compared to referral to treatment as usual (RTAU) for non-treatment seeking college students (N=75) with PTSD symptoms and problem drinking. RESULTS: Overall, the LKM group had low to moderate feasibility and acceptability among college students, as recruitment was lower than expected and attendance at LKM groups was modest. Participants' PTSD symptoms, drinking quantity, and negative drinking consequences decreased, and state mindfulness increased over the course of the study, but there were no significant differences between LKM and RTAU on these outcomes. Additionally, higher coping drinking motives predicted greater PTSD symptoms and more drinking consequences over the course of the study. CONCLUSIONS: Effective interventions for college students with PTSD symptoms and problematic alcohol use are needed, especially for individuals who drink to cope with their PTSD symptoms. Future research on LKM that addresses the limitations of the current study is warranted.

5.
Sci Rep ; 8(1): 6611, 2018 04 26.
Article in English | MEDLINE | ID: mdl-29700375

ABSTRACT

Although several epigenetic modulating drugs are suggested to target cancer stem cells (CSCs), additional identification of anti-CSC drugs is still necessary. Here we showed that JIB-04, a pan-selective inhibitor of histone demethylase(s), was identified as a small molecule that selectively target colorectal CSCs. Our data showed that JIB-04 is capable of reducing self-renewal and stemness of colorectal CSCs in three different colorectal cancer cell lines. JIB-04 significantly attenuated CSC tumorsphere formation, growth/relapse, invasion, and migration in vitro. Furthermore, JIB-04-treated colorectal cancer cells showed reduced tumorigenic activity in vivo. RNA sequencing analysis revealed that JIB-04 affected various cancer-related signaling pathways, especially Wnt/ß-catenin signaling, which is crucial for the proliferation and maintenance of colorectal cancer cells. qRT-PCR and TOP/FOP flash luciferase assays showed that JIB-04 down-regulated the expression of Wnt/ß-catenin-regulated target genes associated with colorectal CSC function. Overall, the effects of JIB-04 were equal to or greater than those of salinomycin, a known anti-colorectal CSC drug, despite the lower concentration of JIB-04 compared with that of salinomycin. Our results strongly suggest that JIB-04 is a promising drug candidate for colorectal cancer therapy.


Subject(s)
Aminopyridines/pharmacology , Colorectal Neoplasms/metabolism , Histone Demethylases/antagonists & inhibitors , Hydrazones/pharmacology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Wnt Signaling Pathway/drug effects , Animals , Biomarkers , Cell Cycle/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Self Renewal/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Models, Animal , Gene Expression , Humans , Mice , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
6.
Exp Cell Res ; 346(1): 30-9, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27256846

ABSTRACT

The scaffold protein BRPF2 (also called BRD1), a key component of histone acetyltransferase complexes, plays an important role in embryonic development, but its function in the differentiation of embryonic stem cells (ESCs) remains unknown. In the present study, we investigated whether BRPF2 is involved in mouse ESC differentiation. BRPF2 depletion resulted in abnormal formation of embryoid bodies, downregulation of differentiation-associated genes, and persistent maintenance of alkaline phosphatase activity even after retinoic acid-induced differentiation, indicating impaired differentiation of BRPF2-depleted ESCs. We also found reduced global acetylation of histone H3 lysine 14 (H3K14) in BRPF2-depleted ESCs, irrespective of differentiation status. Further, co-immunoprecipitation analysis revealed a physical association between BRPF2 and the histone acetyltransferase MOZ in differentiated ESCs, suggesting the role of BRPF2-MOZ complexes in ESC differentiation. Together, these results suggest that BRPF2-MOZ complexes play an important role in the differentiation of ESCs via H3K14 acetylation.


Subject(s)
Cell Differentiation/drug effects , Histone Acetyltransferases/metabolism , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/metabolism , Tretinoin/pharmacology , Acetylation/drug effects , Animals , Gene Expression Regulation, Developmental/drug effects , Gene Knockdown Techniques , HEK293 Cells , Histones/metabolism , Humans , Lysine/metabolism , Mice , Mouse Embryonic Stem Cells/drug effects , Phenotype , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/drug effects , Pluripotent Stem Cells/metabolism , Protein Binding/drug effects , Up-Regulation/drug effects
7.
FEBS Lett ; 589(8): 941-50, 2015 Apr 02.
Article in English | MEDLINE | ID: mdl-25743411

ABSTRACT

The histone acetyltransferase Myst2 plays an important role in embryogenesis, but its function in undifferentiated ES cells remains poorly understood. Here, we show that Myst2 plays a role in pluripotency and self-renewal of ES cells. Myst2 deficiency results in loss of characteristic morphology, decreased alkaline phosphatase staining and reduced histone acetylation, as well as aberrant expression of pluripotency and differentiation markers. Our ChIP data reveal a direct association of Myst2 with the Nanog promoter and Myst2-dependent Oct4 binding on the Nanog promoter. Together our data suggest that Myst2-mediated histone acetylation may be required for recruitment of Oct4 to the Nanog promoter, thereby regulating Nanog transcription in ES cells.


Subject(s)
Embryonic Stem Cells/cytology , Gene Expression Regulation , Histone Acetyltransferases/metabolism , Homeodomain Proteins/genetics , Pluripotent Stem Cells/cytology , Acetylation , Animals , Cell Differentiation , Histone Acetyltransferases/genetics , Histones/metabolism , Humans , Mice , Nanog Homeobox Protein , Octamer Transcription Factor-3/metabolism , Phenotype , Protein Transport
8.
Biol Pharm Bull ; 37(10): 1674-82, 2014.
Article in English | MEDLINE | ID: mdl-25273390

ABSTRACT

To develop an external vehicle for skin hydration and enhanced dermal drug delivery, a hydrogel-based ultra-moisturizing cream (HUMC) was successfully formulated with carbopol 934P, urea, Tinocare GL, grape seed oil, and other excipients. The HUMC showed plastic flow behavior due to a gel structure with a cream base. Different types of drug-free vehicles such as a hydrogel, conventional cream (CC), and three HUMCs were prepared and subjected to an in vivo skin hydration test on a hairless mouse using a corneometer. Hydration effect (∆AU) was in the order of HUMC2>HUMC1 ≥ CC>HUMC3>hydrogel. Using nile red (NR) and 5-carboxyfluorescein (5-CF) as lipophilic and hydrophilic fluorescent probes, respectively, in vitro skin permeation and accumulation studies were conducted using Franz diffusion cells. The values of steady-state flux (Jss, ng/h/cm(2)) were obtained: 74.8 (CC), 145.6 (HUMC1), and 161.9 (HUMC2) for NR delivery; 6.8 (CC), 8.3 (HUMC1), and 10.9 (HUMC2) for 5-CF delivery. The amounts retained in the skin at 12 h (Qr, ng/cm(2)) were determined: 86.4 (CC) and 102.0 (HUMC2) for NR; and 70.1 (CC) and 195.6 (HUMC2) for 5-CF. Confocal microscopy was used to visualize the distribution of the fluorescent probes. NR tended to be localized into the deeper part of the skin with adipose tissue whereas 5-CF localized in the upper layer of the skin. Thus we propose that HUMC2 is an efficacious vehicle for skin hydration and enhances dermal delivery of lipophilic and hydrophilic drugs.


Subject(s)
Drug Delivery Systems/methods , Emollients/administration & dosage , Hydrogel, Polyethylene Glycol Dimethacrylate/administration & dosage , Hypodermoclysis/methods , Skin Absorption/drug effects , Skin Cream/administration & dosage , Administration, Cutaneous , Animals , Emollients/metabolism , Hydrogel, Polyethylene Glycol Dimethacrylate/metabolism , Male , Mice , Mice, Hairless , Organ Culture Techniques , Skin Absorption/physiology , Skin Cream/metabolism
9.
Biol Pharm Bull ; 33(1): 100-6, 2010.
Article in English | MEDLINE | ID: mdl-20045944

ABSTRACT

To develop an external preparation of oregonin (ORG) for the treatment of atopic dermatitis (AD), conventional creams (CC) and elastic liposomes (EL) containing ORG have been formulated and examined for their in vitro skin permeation properties and in vivo therapeutic efficacy assessments. EL, consisting of soybean phosphatidylcholine and Tween 80 (85 : 15 w/w %), were of flexible nanocarriers: they were about 130 nm in size and had a 4-fold greater deformability index than conventional liposomes. In a skin permeation study using a Franz diffusion cell mounted with depilated mouse skin, liposomal systems were superior to cream, revealing greater flux values. Both CC and EL were diversified with the addition of Trans-activating transcriptional activator (Tat) peptide, a sort of cell penetrating peptide, and subjected to in vivo efficacy evaluations in NC/Nga mice with AD-like lesions. On clinical observation for skin severity, rapid and profound improvement was observed in the treatment group with Tat-added liposomes (EL/T), showing a significant difference (p<0.05) versus Tat-added cream. The results indicated that EL/T treatment is effective for normalizing the immune-related responses and alleviating AD, evaluated as changes in the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-4, immunoglobulin E (IgE), and eosinophils in skin or blood.


Subject(s)
Alnus/chemistry , Dermatitis, Atopic/drug therapy , Dermatologic Agents/pharmacology , Diarylheptanoids/therapeutic use , Liposomes , Plant Extracts/therapeutic use , Skin/drug effects , Administration, Topical , Animals , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Dermatologic Agents/administration & dosage , Diarylheptanoids/pharmacology , Dosage Forms , Elasticity , Female , Immune System/drug effects , Male , Mice , Mice, Inbred Strains , Nanostructures , Permeability/drug effects , Phosphatidylcholines , Phytotherapy , Plant Extracts/pharmacology , Polysorbates , Severity of Illness Index , Glycine max/chemistry , Trans-Activators/pharmacology
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