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1.
Int J Mol Sci ; 23(15)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35955780

RESUMO

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.


Assuntos
Neoplasias Ovarianas , Intervenção Coronária Percutânea , Linhagem Celular Tumoral , Feminino , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/genética
2.
J Cell Sci ; 132(3)2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30659116

RESUMO

Heterochromatin protein 1 (HP1) is an epigenetic regulator of chromatin structure and genome function in eukaryotes. Despite shared features, most eukaryotes have a minimum of three HP1 homologs with differential localization patterns and functions. Most studies focus on Drosophila HP1a [also known as Su(var)205], and little is known about the properties of HP1b and HP1c. To determine the features of the three HP1 homologs, we performed the first comprehensive comparative analysis of Drosophila HP1 homologs. HP1 differentially homodimerizes and heterodimerizes in vivo and in vitro HP1b and HP1c, but not HP1a, are localized to both the nucleus and cytoplasm. The C-terminal extension region (CTE) targets HP1c and HP1b to the cytoplasm. Biochemical approaches show that HP1 binds to various interacting partners with different binding affinities. Each HP1 associates differently with RNA polymerase II; a gene reporter assay revealed that HP1a and HP1b, but not HP1c, inhibit transcriptional activity, suggesting that HP1c serves as a positive regulator in transcription. Thus, these studies provide the basic clues pertaining to the molecular mechanism by which HP1 might control cellular processes in a homolog-specific manner.


Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epigênese Genética , Proteínas Nucleares/genética , RNA Polimerase II/genética , Animais , Sítios de Ligação , Homólogo 5 da Proteína Cromobox , Proteínas Cromossômicas não Histona/metabolismo , Clonagem Molecular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Heterocromatina/metabolismo , Heterocromatina/ultraestrutura , Histonas/genética , Histonas/metabolismo , Metilação , Proteínas Nucleares/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , RNA Polimerase II/metabolismo , Homologia de Sequência de Aminoácidos , Transcrição Gênica
3.
FASEB J ; 34(3): 3461-3484, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31961018

RESUMO

The KDM4 subfamily H3K9 histone demethylases are epigenetic regulators that control chromatin structure and gene expression by demethylating histone H3K9, H3K36, and H1.4K26. The KDM4 subfamily mainly consists of four proteins (KDM4A-D), all harboring the Jumonji C domain (JmjC) but with differential substrate specificities. KDM4A-C proteins also possess the double PHD and Tudor domains, whereas KDM4D lacks these domains. KDM4 proteins are overexpressed or deregulated in multiple cancers, cardiovascular diseases, and mental retardation and are thus potential therapeutic targets. Despite extensive efforts, however, there are very few KDM4-selective inhibitors. Defining the exact physiological and oncogenic functions of KDM4 demethylase will provide the foundation for the discovery of novel potent inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM4s and the interplay between KDM4-mediated epigenetic and metabolic pathways in cancer. We also review currently available KDM4 inhibitors and discuss their potential as therapeutic agents for cancer treatment.


Assuntos
Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias/enzimologia , Neoplasias/metabolismo , Animais , Epigênese Genética/genética , Epigênese Genética/fisiologia , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias/genética , Domínios Proteicos
4.
Int J Mol Sci ; 22(22)2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34830173

RESUMO

As major components of spider venoms, neurotoxic peptides exhibit structural diversity, target specificity, and have great pharmaceutical potential. Deep learning may be an alternative to the laborious and time-consuming methods for identifying these peptides. However, the major hurdle in developing a deep learning model is the limited data on neurotoxic peptides. Here, we present a peptide data augmentation method that improves the recognition of neurotoxic peptides via a convolutional neural network model. The neurotoxic peptides were augmented with the known neurotoxic peptides from UniProt database, and the models were trained using a training set with or without the generated sequences to verify the augmented data. The model trained with the augmented dataset outperformed the one with the unaugmented dataset, achieving accuracy of 0.9953, precision of 0.9922, recall of 0.9984, and F1 score of 0.9953 in simulation dataset. From the set of all RNA transcripts of Callobius koreanus spider, we discovered neurotoxic peptides via the model, resulting in 275 putative peptides of which 252 novel sequences and only 23 sequences showing homology with the known peptides by Basic Local Alignment Search Tool. Among these 275 peptides, four were selected and shown to have neuromodulatory effects on the human neuroblastoma cell line SH-SY5Y. The augmentation method presented here may be applied to the identification of other functional peptides from biological resources with insufficient data.


Assuntos
Bases de Dados de Proteínas , Aprendizado Profundo , Neurotoxinas , Peptídeos , Venenos de Aranha , Aranhas , Animais , Neurotoxinas/química , Neurotoxinas/genética , Peptídeos/química , Peptídeos/genética , Venenos de Aranha/química , Venenos de Aranha/genética , Aranhas/química , Aranhas/genética
5.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572814

RESUMO

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.


Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Bortezomib/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Linhagem Celular Tumoral , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Humanos , Mieloma Múltiplo/metabolismo
6.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567690

RESUMO

The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.


Assuntos
Antineoplásicos/farmacologia , Glutamato-Amônia Ligase/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos , Neoplasias/enzimologia , Neoplasias/patologia
7.
Korean J Physiol Pharmacol ; 25(4): 333-339, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34187950

RESUMO

Injection lipolysis or mesotherapy gained popularity for local fat dissolve as an alternative to surgical liposuction. Phosphatidylcholine (PPC) and aminophylline (AMPL) are commonly used compounds for mesotherapy, but their efficacy and safety as lipolytic agents have been controversial. Glycerophosphocholine (GPC) is a choline precursor structurally similar to PPC, and thus introduced in aesthetics as an alternative for PPC. This study aimed to evaluate the effects of GPC on adipocytes differentiation and lipolysis and compared those effects with PPC and AMPL using in vitro and in vivo models. Adipogenesis in 3T3-L1 was measured by Oil Red O staining. Lipolysis was assessed by measuring the amount of glycerol released in the culture media. To evaluate the lipolytic activity of GPC on a physiological condition, GPC was subcutaneously injected to one side of inguinal fat pads for 3 days. Lipolytic activity of GPC was assessed by hematoxylin and eosin staining in adipose tissue. GPC significantly suppressed adipocyte differentiation of 3T3-L1 in a concentration-dependent manner (22.3% inhibition at 4 mM of GPC compared to control). Moreover, when lipolysis was assessed by glycerol release in 3T3-L1 adipocytes, 6 mM of GPC stimulated glycerol release by two-fold over control. Subcutaneous injection of GPC into the inguinal fat pad of mice significantly reduced the mass of fat pad and the size of adipocytes of injected site, and these effects of GPC were more prominent over PPC and AMPL. Taken together, these results suggest that GPC is the potential therapeutic agent as a local fat reducer.

8.
Int J Mol Sci ; 21(17)2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32825184

RESUMO

Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cisplatino/toxicidade , Resistencia a Medicamentos Antineoplásicos , Enzimas de Conjugação de Ubiquitina/metabolismo , Neoplasias do Colo do Útero/metabolismo , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Ácidos Graxos Insaturados/farmacologia , Feminino , Células HeLa , Humanos , Proteína Supressora de Tumor p53/metabolismo , Enzimas de Conjugação de Ubiquitina/genética
9.
Int J Mol Sci ; 21(18)2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32961679

RESUMO

Overexpression of histone deacetylase 6 (HDAC6) and bromodomain-containing protein 4 (BRD4) is related to aggressiveness of head and neck squamous carcinoma (HNSCC). Based on studies that HDAC6 and BRD4 are potential therapeutic targets of HNSCC, we hypothesized that the combination treatment of BET inhibitor JQ1 and HDAC6-selective inhibitor ACY-241 could exhibit synergistic anticancer effects in human papillomavirus (HPV)-positive and HPV-negative HNSCC cells. In this study, HNSCC cell growth and viability were measured by CCK-8 assay, apoptosis was analyzed by flow cytometry, and metastasis was studied by wound healing and transwell assays. Furthermore, immunoblotting is conducted to investigate proteins that modulate apoptosis or metastasis. Here, we report that the combination of ACY-241 and JQ1 shows synergistic cell growth inhibition, viability reduction, and apoptosis induction in HNSCC cells through inactivation of AKT and NF-κB signaling. Importantly, we demonstrate that combined treatment of ACY-241 and JQ1 synergistically suppresses TNF-α-induced migration and invasion via dysregulating matrix metalloproteinase (MMP)-2, MMP-9, and MT1-MMP. Overall, the combination of ACY-241 and JQ1 significantly suppresses proliferation and metastasis in HPV-positive and HPV-negative HNSCC. Collectively, these findings suggest that the co-inhibition of BET and HDAC6 can be a new therapeutic strategy in HNSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Proteínas de Neoplasias/biossíntese , Carcinoma de Células Escamosas de Cabeça e Pescoço , Azepinas/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Neoplásica , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Triazóis/farmacologia
10.
Mol Carcinog ; 58(6): 944-956, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30693983

RESUMO

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL) with genetic alterations of BCL-2, KMT2B, and KMT6. FL is refractory to conventional chemotherapy and is still incurable in most patients. Thus, new drugs and/or novel combination treatment strategies are needed to further improve FL patient outcome. We investigated the efficacy of the histone deacetylase 6 (HDAC6) inhibitor A452 combined with a Bruton's tyrosine kinase (BTK) inhibitor ibrutinib on NHL and the underlying mechanisms compared with the current clinically tested HDAC6 inhibitor ACY-1215. We first showed that FL is the most sensitive to HDAC6 inhibitor. We showed that combining A452 with ibrutinib led to the synergistic inhibition of cell growth and decreased viability of FL cells, as well as increased levels of apoptosis. Similar synergistic interactions occur in chronic lymphocytic leukemia (CLL) and germinal center diffuse large B-cell lymphoma cells (DLBCL). Enhanced cell death is associated with AKT and ERK1/2 inactivation and increased DNA damage (induction of γH2A.X and reduction of pChk1/2). In addition, A452 downregulates c-Myc, an effect significantly enhanced by ibruninib. Although ACY-1215 is less potent than A452, it displays synergism with ibrutinib. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215 in FL. These findings suggest that a combination of HDAC6-selective inhibitor and ibrutinib is a potent therapeutic strategy for NHL including FL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Linfoma Folicular/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/farmacologia , Linfoma Folicular/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piperidinas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
11.
Trends Biochem Sci ; 36(4): 211-20, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21075636

RESUMO

Recent proteomic studies reveal that 5-10% of mammalian and bacterial proteins undergo lysine acetylation, a post-translational modification that adds an acetyl group to the ɛ-amino group of lysine residues. Many of these proteins are not canonical targets, such as histones and transcription factors, suggesting that this modification plays a much wider role than previously appreciated. These studies also suggest that lysine acetylomes are at least comparable with (if not larger than) phosphoproteomes. Although many of the newly identified acetylation events still require validation, they constitute an important framework for further research and the development of new drugs useful in treating a variety of pathologies. Herein, we summarize these proteomic studies and highlight recent reports linking lysine acetylation to heterochromatin assembly, sister chromatid cohesion, cytoskeleton dynamics, autophagy, receptor signaling, RNA processing and metabolic control.


Assuntos
Bactérias/metabolismo , Acetato-CoA Ligase/metabolismo , Acetilação , Animais , Humanos , Lisina/metabolismo , Proteoma/metabolismo
12.
Ann Surg Oncol ; 22(9): 3049-54, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25608771

RESUMO

BACKGROUND: This study aimed to determine the incidence, risk factors, and prognostic significance of retropharyngeal lymph node (RPLN) metastasis from malignancies of the oropharynx. METHODS: The study retrospectively analyzed 54 patients with oropharyngeal squamous cell carcinoma who underwent primary surgery-based treatment. Most of the patients had advanced stage (stage 3 or 4, 96.3 %) oropharyngeal cancer. Surgery alone was performed for 14 patients. Postoperative radiotherapy was administered to 14 patients and chemoradiation to 26 patients. Genotyping and detection of human papillomavirus (HPV) was available for 52 patients. RESULTS: Using pathologic analysis, RPLN metastasis was confirmed in 22 subjects. The patients with RPLN metastasis had a significantly lower disease-specific survival rate than the non-RPLN metastasis group (54.5 vs 75 %; p = 0.05). The pN+ (RPLN) yield of these cases was 18/22 (81.8 %) for cN+ (RPLN) versus 4/32 (7.4 %) for cN0 (RPLN). Multivariate analysis identified the independent factors associated with RPLN metastasis as radiographically positive retropharyngeal node (p = 0.012; odds ratio [OR] 53.920) and posterior pharyngeal wall invasion (p = 0.021; OR 33.014). A high-risk HPV-positive result was not significantly correlated with RPLN metastasis. CONCLUSIONS: Elective RPLN dissection should be considered for patients with advanced neck and primary tumor, particularly those with posterior pharyngeal wall invasion.


Assuntos
Carcinoma de Células Escamosas/secundário , Neoplasias Hipofaríngeas/patologia , Neoplasias Orofaríngeas/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hipofaríngeas/cirurgia , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/cirurgia , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
13.
J Biol Chem ; 288(28): 20334-50, 2013 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-23720746

RESUMO

α-Tubulin acetylation at Lys-40, located on the luminal side of microtubules, has been widely studied and used as a marker for stable microtubules in the cilia and other subcellular structures, but the functional consequences remain perplexing. Recent studies have shown that Mec-17 and its paralog are responsible for α-tubulin acetylation in Caenorhabditis elegans. There is one such protein known as Atat1 (α-tubulin acetyltransferase 1) per higher organism. Zebrafish Atat1 appears to govern embryo development, raising the intriguing possibility that Atat1 is also critical for development in mammals. In addition to Atat1, three other mammalian acetyltransferases, ARD1-NAT1, ELP3, and GCN5, have been shown to acetylate α-tubulin in vitro, so an important question is how these four enzymes contribute to the acetylation in vivo. We demonstrate here that Atat1 is a major α-tubulin acetyltransferase in mice. It is widely expressed in mouse embryos and tissues. Although Atat1-null animals display no overt phenotypes, α-tubulin acetylation is lost in sperm flagella and the dentate gyrus is slightly deformed. Furthermore, human ATAT1 colocalizes on bundled microtubules with doublecortin. These results thus suggest that mouse Atat1 may regulate advanced functions such as learning and memory, thereby shedding novel light on the physiological roles of α-tubulin acetylation in mammals.


Assuntos
Acetiltransferases/metabolismo , Giro Denteado/metabolismo , Tubulina (Proteína)/metabolismo , Acetilação , Acetiltransferases/genética , Animais , Western Blotting , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Células Cultivadas , Giro Denteado/anormalidades , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Proteínas dos Microtúbulos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cauda do Espermatozoide/metabolismo , Testículo/embriologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Fatores de Tempo
14.
J Biol Chem ; 288(8): 5591-605, 2013 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-23297420

RESUMO

Histone deacetylase 4 (HDAC4) and its paralogs, HDAC5, -7, and -9 (all members of class IIa), possess multiple phosphorylation sites crucial for 14-3-3 binding and subsequent nuclear export. cAMP signaling stimulates nuclear import of HDAC4 and HDAC5, but the underlying mechanisms remain to be elucidated. Here we show that cAMP potentiates nuclear localization of HDAC9. Mutation of an SP motif conserved in HDAC4, -5, and -9 prevents cAMP-stimulated nuclear localization. Unexpectedly, this treatment inhibits phosphorylation at the SP motif, indicating an inverse relationship between the phosphorylation event and nuclear import. Consistent with this, leptomycin B-induced nuclear import and adrenocorticotropic hormone (ACTH) treatment result in the dephosphorylation at the motif. Moreover, the modification synergizes with phosphorylation at a nearby site, and similar kinetics was observed for both phosphorylation events during myoblast and adipocyte differentiation. These results thus unravel a previously unrecognized mechanism whereby cAMP promotes dephosphorylation and differentially regulates multisite phosphorylation and the nuclear localization of class IIa HDACs.


Assuntos
AMP Cíclico/metabolismo , Histona Desacetilases/biossíntese , Células 3T3 , Transporte Ativo do Núcleo Celular , Motivos de Aminoácidos , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoplasma/metabolismo , Células HEK293 , Células HeLa , Histona Desacetilases/química , Humanos , Insetos , Camundongos , Fosforilação , Plasmídeos/metabolismo , Transdução de Sinais
15.
J Biol Chem ; 288(13): 9345-62, 2013 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-23393134

RESUMO

Histone deacetylases 4 (HDAC4), -5, -7, and -9 form class IIa within the HDAC superfamily and regulate diverse physiological and pathological cellular programs. With conserved motifs for phosphorylation-dependent 14-3-3 binding, these deacetylases serve as novel signal transducers that are able to modulate histone acetylation and gene expression in response to extracellular cues. Here, we report that in a PKA-sensitive manner the tumor suppressor kinase LKB1 acts through salt-inducible kinase 2 (SIK2) and SIK3 to promote nucleocytoplasmic trafficking of class IIa HDACs. Both SIK2 and SIK3 phosphorylate the deacetylases at the conserved motifs and stimulate 14-3-3 binding. SIK2 activates MEF2-dependent transcription and relieves repression of myogenesis by the deacetylases. Distinct from SIK2, SIK3 induces nuclear export of the deacetylases independent of kinase activity and 14-3-3 binding. These findings highlight the difference among members of the SIK family and indicate that LKB1-dependent SIK activation constitutes an important signaling module upstream from class IIa deacetylases for regulating cellular programs controlled by MEF2 and other transcription factors.


Assuntos
Histona Desacetilases/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas 14-3-3/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP , Animais , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoplasma/metabolismo , Genes Reporter , Células HEK293 , Células HeLa , Humanos , Camundongos , Ligação Proteica , Transdução de Sinais
16.
Biol Pharm Bull ; 37(8): 1341-51, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25087956

RESUMO

Beneficial effect of eugenol on fatty liver was examined in hepatocytes and liver tissue of high fat diet (HFD)-fed C57BL/6J mice. To induce a fatty liver, palmitic acid or isolated hepatocytes from HFD-fed Sprague-Dawley (SD) rats were used in vitro studies, and C57BL/6J mice were fed HFD for 10 weeks. Lipid contents were markedly decreased when hepatocytes were treated with eugenol for up to 24 h. Gene expressions of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes were suppressed but those of lipolysis-related proteins were increased. As a regulatory kinase for lipogenic transcriptional factors, the AMP-activated protein kinase (AMPK) signaling pathway was examined. Protein expressions of phosphorylated Ca(2+)-calmodulin dependent protein kinase kinase (CAMKK), AMPK and acetyl-CoA carboxylase (ACC) were significantly increased and those of phosphorylated mammalian target of rapamycin (mTOR) and p70S6K were suppressed when the hepatocytes were treated with eugenol at up to 100 µM. These effects were all reversed in the presence of specific inhibitors of CAMKK, AMPK or mTOR. In vivo studies, hepatic triglyceride (TG) levels and steatosis score were decreased by 45% and 72%, respectively, in eugenol-treated mice. Gene expressions of fibrosis marker protein such as α-smooth muscle actin (α-SMA), collagen type I (Col-I) and plasminogen activator inhibitor-1 (PAI-1) were also significantly reduced by 36%, 63% and 40% in eugenol-treated mice. In summary, eugenol may represent a potential intervention in populations at high risk for fatty liver.


Assuntos
Eugenol/farmacologia , Fígado Gorduroso/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Actinas/genética , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Colágeno Tipo I/genética , Regulação para Baixo , Eugenol/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fibrose , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Inibidor 1 de Ativador de Plasminogênio/genética , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo
17.
Eur Arch Otorhinolaryngol ; 271(12): 3179-85, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24258852

RESUMO

The purpose of this study was to investigate the characteristics of external auditory canal cholesteatoma (EACC) in children through evaluation of the clinical and radiologic features as well as treatment outcomes. The clinical records were retrospectively reviewed for children under 15 years of age diagnosed with spontaneous EACC between March 2004 and December 2011. The clinical data of adults diagnosed with spontaneous EACC during the same period were evaluated to compare with EACC in children. Eight patients (3 males and 5 females) with pediatric EACC and 18 patients (7 males and 11 females, 20 ears) with adult EACC were included within the boundary of the study. The mean ages were 12.4 years (age range 9-15) for pediatric EACC and 49.8 years (age range 29-79) for adult EACC patients. Follow-up periods ranged from 8 to 86 months (mean 32.5 ± 8.62) in pediatric EACC and from 6 to 72 months (mean 22.2 ± 5.36) in adult EACC. Pediatric EACC, showed involvement most commonly in the posterior wall, while the inferior wall was most commonly involved in adult EACC. Pediatric EACC tended to show a more focal involvement and was not as extensive as adult EACC. Extension into the adjacent structures was similar in both groups, but bony destruction was more common in the adult group. Two children and eight adult patients were treated with surgery, but four adult cases needed more extensive surgical treatment because their disease was widely spread to included areas such as the mastoid segment of facial nerve and the temporomandibular joint. Six pediatric cases treated with conservative management showed no progression of disease on physical examination at the last visit, but two cases of adults progressed and required canaloplasty. Pediatric EACC shows less aggressive behavior compared to adult EACC. Adequate management may work better in pediatric than in adult EACC, even though the treatment modality is conservative management.


Assuntos
Colesteatoma , Desbridamento/métodos , Meato Acústico Externo , Procedimentos Cirúrgicos Otológicos/métodos , Adolescente , Adulto , Fatores Etários , Criança , Colesteatoma/diagnóstico , Colesteatoma/fisiopatologia , Colesteatoma/cirurgia , Gerenciamento Clínico , Progressão da Doença , Meato Acústico Externo/diagnóstico por imagem , Meato Acústico Externo/patologia , Nervo Facial/patologia , Feminino , Humanos , Masculino , Processo Mastoide/patologia , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Exame Físico , Radiografia , Estudos Retrospectivos , Índice de Gravidade de Doença
18.
Cell Death Dis ; 15(6): 451, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38926399

RESUMO

Advances in functional studies on epigenetic regulators have disclosed the vital roles played by diverse histone lysine demethylases (KDMs), ranging from normal development to tumorigenesis. Most of the KDMs are Jumonji C domain-containing (JMJD) proteins. Many of these KDMs remove methyl groups from histone tails to regulate gene transcription. There are more than 30 known KDM proteins, which fall into different subfamilies. Of the many KDM subfamilies, KDM3 (JMJD1) proteins specifically remove dimethyl and monomethyl marks from lysine 9 on histone H3 and other non-histone proteins. Dysregulation of KDM3 proteins leads to infertility, obesity, metabolic syndromes, heart diseases, and cancers. Among the KDM3 proteins, KDM3A has been largely studied in cancers. However, despite a number of studies pointing out their importance in tumorigenesis, KDM3B and KDM3C are relatively overlooked. KDM3B and KDM3C show context-dependent functions, showing pro- or anti-tumorigenic abilities in different cancers. Thus, this review provides a thorough understanding of the involvement of KDM3B and KDMC in oncology that should be helpful in determining the role of KDM3 proteins in preclinical studies for development of novel pharmacological methods to overcome cancer.


Assuntos
Carcinogênese , Epigênese Genética , Histona Desmetilases com o Domínio Jumonji , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Carcinogênese/genética , Carcinogênese/patologia , Carcinogênese/metabolismo , Animais , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia
19.
Korean J Physiol Pharmacol ; 17(5): 447-53, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24227947

RESUMO

Osteoblastic activity of nectandrin A was examined in C2C12 cells. Nectandrin A enhances the BMP-induced osteoblastic differentiation and mineralization, manifested by the up-regulation of differentiation markers (alkaline phosphatase and osteogenic genes) and increased calcium contents. In C2C12 cells co-transfected with expression vector encoding Smad4 and Id1-Luc reporter, nectandrin A increased Id1 luciferase activity in a concentration-dependent manner, when compared to that in BMP-2 treated cells, indicating that Smad signaling pathway is associated with nectandrin A-enhanced osteoblastic differentiation in C2C12 cells. In addition, nectandrin A activated p38 mitogen-activated protein kinase (MAPK) in time- and concentration-dependent manners, and phosphorylated form of pSmad1/5/8 and alkaline phosphatase activity were both decreased when the cells were pretreated with SB203580, a p38 MAPK inhibitor, suggesting that p38 MAPK might be an upstream kinase for Smad signaling pathway. Taken together, nectandrin A enhances the BMP-induced osteoblastic differentiation and mineralization of C2C12 cells via activation of p38 MAPK-Smad signaling pathway, and it has a therapeutic potential for osteoporosis by promoting bone formation.

20.
Cancers (Basel) ; 15(4)2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36831463

RESUMO

Melanoma is the most lethal type of skin cancer, and it causes more than 55,000 deaths annually. Although regional melanoma can be surgically removed, once melanoma metastasizes to other regions of the body, the survival rate drops dramatically. The current treatment options are chemotherapy, immunotherapy, and targeted therapy. However, the low response rate and the development of resistance necessitate the search for a novel therapeutic target in melanoma. Hypoxia-inducible factor-1 α (HIF-1α) is overexpressed in melanoma and plays a crucial role in driving malignant transformation in cancer cells. Here, we identified that histone deacetylase 8 (HDAC8) enhances the protein stability of HIF-1α. HDAC8 directly binds to and deacetylates HIF-1α, thereby promoting its protein stability. This, in turn, upregulates the transcriptional activity of HIF-1α and promotes the expressions of its target genes, such as hexokinase 2 (HK2) and glucose transporter 1 (GLUT1). The inhibition of HDAC8 suppresses the proliferation and metastasis of melanoma cells. Furthermore, HDAC8 is correlated with HIF1A expression and poor prognosis in samples from patients with melanoma. These findings uncover a novel epigenetic mechanism that maintains HIF-1α stability and implicates the potential of HDAC8 inhibitors for melanoma therapy.

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