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1.
Life Sci Alliance ; 6(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36414381

RESUMO

Enhanced fatty acid synthesis is a hallmark of tumors, including glioblastoma. SREBF1/2 regulate the expression of enzymes involved in fatty acid and cholesterol synthesis. Yet, little is known about the precise mechanism regulating SREBP gene expression in glioblastoma. Here, we show that a novel interaction between the co-activator/co-repressor CTBP and the tumor suppressor ZBTB18 regulates the expression of SREBP genes. In line with our findings, metabolic assays and glucose tracing analysis confirm the reduction in several phospholipid species upon ZBTB18 expression. Our study identifies CTBP1/2 and LSD1 as co-activators of SREBP genes and indicates that the functional activity of the CTBP-LSD1 complex is altered by ZBTB18. ZBTB18 binding to the SREBP gene promoters is associated with reduced LSD1 demethylase activity of H3K4me2 and H3K9me2 marks. Concomitantly, the interaction between LSD1, CTBP, and ZNF217 is increased, suggesting that ZBTB18 promotes LSD1 scaffolding function. Our results outline a new epigenetic mechanism enrolled by ZBTB18 and its co-factors to regulate fatty acid synthesis that could be targeted to treat glioblastoma patients.


Assuntos
Glioblastoma , Humanos , Glioblastoma/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Lipídeos , Ácidos Graxos
2.
BMC Cancer ; 22(1): 1166, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36368958

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC), originating from the bile ducts, is the second most common primary liver malignancy, and its incidence has recently increased. H2A.Z, a highly conserved H2A variant, is emerging as a key regulatory molecule in cancer. However, its underlying mechanism of action in ICC cells remains unclear.  METHODS: Here, we examined the expression of H2A.Z and SFRP1 in normal intrahepatic cholangiocytes, ICC cell lines, ICC tissue microarrays, and fresh specimens. The correlations between H2A.Z or SFRP1 expression and clinical features were analysed. The overall survival rate was analysed based on H2A.Z and SFRP1 expression. Immunoprecipitation was used to analyse the recruitment of KDM1A, and ChIP sequencing and BSP were used to analyse the enrichment of methylation-related molecules such as H3K4me1 and H3K4me2 in the SFRP1 promoter and reveal the underlying mechanisms. Knockdown and rescue experiments were used to determine the potential mechanism by which H2A.Z and SFRP1 promote tumorigenesis in vitro. RESULTS: We showed that upregulation of H2A.Z expression is linked to downregulation of SFRP1 expression in ICC tissues and poor overall survival in patients with ICC. H2A.Z interacted with KDM1A in the nucleus to bind to the -151 ~ -136 bp region upstream of the SFRP1 promoter to increase its demethylation in ICC cells. Functionally, H2A.Z silencing inhibited the proliferation and invasion of ICC cells, and these effects were mitigated by SFRP1 silencing in ICC cells. CONCLUSIONS: Our findings reveal that H2A.Z inhibits SFRP1 expression through chromatin modification in the context of ICC by forming a complex with KDM1A in the nucleus.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Metilação , Colangiocarcinoma/patologia , Histonas/metabolismo , Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Linhagem Celular Tumoral , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo
3.
Nat Struct Mol Biol ; 29(11): 1122-1135, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36344844

RESUMO

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER+ breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit LSD1. Genetic and pharmacological CoREST inhibition reduces tumorigenesis and metastasis of endocrine-sensitive and endocrine-resistant xenograft models. Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Cromatina , Carcinogênese
4.
Sci Rep ; 12(1): 19168, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357457

RESUMO

Ferroptosis is a cell death process caused by metabolic dysfunction with the feature of aberrant iron accumulation. Emerging studies have identified that ferroptosis is an important biological function involving in the tumorigenesis, and targeting ferroptosis could provide promising therapeutic targets for lung cancer. However, such therapeutic strategies show limited therapeutic effect owing to drug resistance and other unknown underlying mechanisms. In this study, lysine-specific demethylase 1 (LSD1/KDM1A) was found to be significantly upregulated in lung cancer cells and tissues. The patients with KDM1A downregulation displayed the good prognosis. Using gene set enrichment analysis (GSEA), we demonstrated that KDM1A-associated genes might participate in the regulation of cell ferroptosis and Myc signaling in lung cancer. Knockdown of KDM1A inhibited the level of c-Myc and increased the concentration of malondialdehyde (MDA) and irons in human lung cancer cells H1299 and A549. Downregulation of c-Myc could facilitate KDM1A knockdown-mediated ferroptosis. Our study has elucidated the effect of KDM1A/c-Myc regulatory axis in the ferroptosis resistance of lung cancer cells.


Assuntos
Ferroptose , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ferroptose/genética , Linhagem Celular Tumoral , Transdução de Sinais , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo
5.
Cell Death Dis ; 13(10): 843, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192394

RESUMO

Abnormality of enhancer regulation has emerged as one of the critical features for cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast cancer tumorigenesis and development.


Assuntos
Histonas , Neoplasias , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas/metabolismo
6.
Cancer Res ; 82(22): 4247-4260, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36306422

RESUMO

Lysine (K)-specific demethylase 6A (KDM6A) is a frequently mutated tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC). However, the impact of KDM6A loss on the PDAC tumor immune microenvironment is not known. This study used a genetically engineered, pancreas-specific Kdm6a knockout (KO) PDAC mouse model and human PDAC tissue samples to demonstrate that KDM6A loss correlates with increased tumor-associated neutrophils and neutrophil extracellular traps (NET) formation, which are known to contribute to PDAC progression. Genome-wide bromouridine sequencing analysis to evaluate nascent RNA synthesis showed that the expression of many chemotactic cytokines, especially CXC motif chemokine ligand 1 (CXCL1), was upregulated in KDM6A KO PDAC cells. KDM6A-deficient PDAC cells secreted higher levels of CXCL1 protein, which in turn recruited neutrophils. Furthermore, in a syngeneic orthotopic mouse model, treatment with a CXCL1 neutralizing antibody blocked the chemotactic and NET-promoting properties of KDM6A-deficient PDAC cells and suppressed tumor growth, confirming CXCL1 as a key mediator of chemotaxis and PDAC growth driven by KDM6A loss. These findings shed light on how KDM6A regulates the tumor immune microenvironment and PDAC progression and suggests that the CXCL1-CXCR2 axis may be a candidate target in PDAC with KDM6A loss. SIGNIFICANCE: KDM6A loss in pancreatic cancer cells alters the immune microenvironment by increasing CXCL1 secretion and neutrophil recruitment, providing a rationale for targeting the CXCL1-CXCR2 signaling axis in tumors with low KDM6A.


Assuntos
Carcinoma Ductal Pancreático , Armadilhas Extracelulares , Histona Desmetilases , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Carcinoma Ductal Pancreático/patologia , Armadilhas Extracelulares/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Neutrófilos/metabolismo , Neoplasias Pancreáticas/patologia , Microambiente Tumoral
7.
Int J Mol Sci ; 23(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36232341

RESUMO

Environmental factors that have been linked to an increased endometriosis risk include exposure to di-(2-ethylhexyl)-phthalate (DEHP), an endocrine disruptor. This study aims to investigate whether DEHP in vitro exposure in primary endometrial stromal cells (EnSC), primary endometrial epithelial cells (EnEC), and the human endometrial adenocarcinoma cell line Ishikawa properly mimics alterations described in the eutopic endometrium of women with endometriosis. Primary EnSC and EnEC, isolated from six fertile egg donors, and Ishikawa cells were exposed to DEHP (0.1, 1, and 10 µM) and were assessed for viability, endometriosis markers (IL-6, VEGF-A, HOXA10, EZH2, and LSD1), steroid receptor gene expressions (ER-1, ER-2, PR-T, PR-B, and PGRMC1), and invasive capacity. Viability after 72 h of DEHP exposure was not significantly affected. None of the endometriosis markers studied were altered after acute DEHP exposure, nor was the expression of steroid receptors. The invasive capacity of EnSC was significantly increased after 10 µM of DEHP exposure. In conclusion, acute DEHP exposure in primary endometrial cells does not fully phenocopy the changes in the viability, expression of markers, or steroidal receptors described in endometriosis. However, the significant increase in EnSC invasiveness observed after DEHP exposure could be a link between DEHP exposure and increased endometriosis likelihood.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Endometriose , Receptores de Esteroides , Dietilexilftalato/metabolismo , Disruptores Endócrinos/farmacologia , Endometriose/induzido quimicamente , Endometriose/metabolismo , Endométrio/metabolismo , Feminino , Histona Desmetilases/metabolismo , Humanos , Interleucina-6/metabolismo , Proteínas de Membrana/metabolismo , Ácidos Ftálicos , Receptores de Progesterona/metabolismo , Receptores de Esteroides/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Anal Cell Pathol (Amst) ; 2022: 2522597, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36276611

RESUMO

Background and Purpose. Breast cancer ranks first in the incidence of female tumors. Triple-negative breast cancer (TNBC), one type of breast cancer, is more aggressive and has a worse prognosis. Demethylzeylasteral (T-96) is isolated from Tripterygium wilfordii Hook F. Our previous study found that T96 could inhibit TNBC invasion via suppressing the canonical and noncanonical TGF-ß signaling pathways. However, the antitumor effects and mechanisms of T-96 on TNBC have not been studied. This study is aimed at investigating the antitumor effect and mechanism of T-96 on breast cancer. Experimental approach. MTT assay, Live and Dead cell assay, and TUNEL were used to observe the antitumor effect of breast cancer cells treated with T-96. siRNA of LSD1, Co-IP, and molecular docking were used to explore the direct target and mechanism of T-96. Subcutaneous murine xenograft models were used to detect the efficacy of T-96 antitumor activity in vivo. Key Results. T-96 was more susceptible to inducing the apoptosis of highly metastatic TNBC cell lines (SUM-1315). An abnormal level of histone methylation is a crucial characteristic of metastatic cancer cells. LSD1 is a histone demethylase. We found that T-96 could significantly decrease the protein expression of LSD1, increase its target protein PTEN expression and enhance histone methylation. T-96 could also down-regulate the PI3K/AKT signaling pathway, which could be blocked by PTEN. Knockdown of LSD1 by siRNA blocked the pharmacological activity of T-96. And the molecular docking predicted T-96 processed affinity toward LSD1 through hydrogen bonding. Finally, T-96 was evaluated in a murine xenograft model of SUM-1315 cells. And T-96 could significantly inhibit tumor growth without showing marked toxicity. Conclusions & Implications. The results illustrated that T-96 exerted antitumor activity in highly metastatic TNBC by inactivating the LSD1 function.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Camundongos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , RNA Interferente Pequeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Histonas/genética , Histonas/metabolismo , Histonas/farmacologia , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Apoptose , Epigênese Genética , Fator de Crescimento Transformador beta/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células
9.
Asian Pac J Cancer Prev ; 23(10): 3533-3540, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36308380

RESUMO

BACKGROUND: Lysine-specific demethylase is a demethylase enzyme that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. LSD1 is associated with its corepressor protein CoREST, and utilizes tetrahydrofolate as a cofactor to accept CH2 from the demethylation process. The fact that the cofactor is best bound to the active site inspired us to explore its interactions to LSD1/CoREST enzyme complex utilizing molecular dynamics simulation, which aids designing novel and potent inhibitors. OBJECTIVE: In this study we minted to identify a new potential LSD1/CoREST inhibitors and test the potency and the safety of such inhibitors against human neuroblastoma and fibroblast cells lines. METHODS: We have implemented a previously derived model from the molecular dynamics simulation study and the key contacts to the active site in a subsequent structure based drug design and in-silico screening, which revealed a number of potential inhibitors toward LSD1/CoREST complex. The anti-proliferative activities of the identified compounds will be tested against neuroblastoma SH-SY5Y cancer cell line which known to highly express LSD1/CoREST complex. RESULTS: In-silico mining on National Cancer Institute (NCI) database identified 55 promising and structurally diverse inhibitors. Applying the abovementioned molecular modeling procedure yielded four compounds of LSD1/CoREST inhibiters with IC50 < 2µM. The four lead compounds were tested against SH-SY5Y neuroblastoma cell line that known to express high level of LSD1 and illustrated a potent activity with an IC50 ranging from 0.195 to 1.52µM. To estimate the toxicity of the selective leads, they were tested against normal fibroblast cells and scored a relatively high IC50 ranging from 0.303 to ≥ 100µM. CONCLUSION: Our model revealed promising inhibitors that can be used in treating cancers that overexpress the LSD1 enzyme such as the SH-SY5Y neuroblastoma.


Assuntos
Simulação de Dinâmica Molecular , Neuroblastoma , Humanos , Histona Desmetilases/química , Histona Desmetilases/metabolismo , Ligação Proteica , Neuroblastoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Histonas/metabolismo , Linhagem Celular , Inibidores Enzimáticos
10.
Biochem Biophys Res Commun ; 628: 104-109, 2022 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-36084547

RESUMO

Metastasis is a major cause of breast cancer mortality and the current study found histone demethylase, KDM2A, expression to be negatively correlated with breast cancer metastasis. KDM2A knockdown greatly promoted migration and invasion of breast cancer cells. The histone demethylase activity of KDM2A downregulated EGF transcription and suppressed the EGF-TSPAN8 pathway. Inhibition of breast cancer cell migration was also dependent on the histone demethylase activity of KDM2A. A novel mechanism of KDM2A-suppression of the EGF-TSPAN8 pathway which inhibited breast cancer cell migration and invasion is reported.


Assuntos
Neoplasias da Mama , Proteínas F-Box , Histona Desmetilases com o Domínio Jumonji , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Tetraspaninas/metabolismo
11.
Oncogene ; 41(41): 4633-4644, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088505

RESUMO

Obesity is associated with increased prostate cancer (PCa) progression and higher mortality, however, the mechanism(s) remain still unclear. Here, we investigated signaling by the ASC-secreted chemokine CXCL12 in a mouse allograft model of PCa and in HiMyc mice in the context of diet-induced obesity. Treatment of mice with CXCR4 antagonist inhibited CXCL12-induced signaling pathways, tumor growth and EMT in HMVP2 allograft tumors. Similar results were obtained following prostate epithelium-specific deletion of CXCR4 in HiMyc mice. We also show that CXCR4 signaling regulates expression of JMJD2A histone demethylase and histone methylation which is modulated by AMD3100. Importantly, treatment with a CXCR7 antagonist also inhibited allograft tumor growth and EMT. The current results demonstrate that both CXCR4 and CXCR7 play an important role in cancer progression and establish CXCL12 signaling pathways, activated in obesity, as potential targets for PCa intervention. In addition, other factors secreted by ASCs, may also contribute to cancer aggressiveness in obesity.


Assuntos
Neoplasias da Próstata , Receptores CXCR , Animais , Linhagem Celular Tumoral , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Transição Epitelial-Mesenquimal , Histona Desmetilases/metabolismo , Histonas , Masculino , Camundongos , Obesidade/genética , Próstata/patologia , Neoplasias da Próstata/patologia , Receptores CXCR4/metabolismo
12.
Oncogene ; 41(44): 4841-4854, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36171271

RESUMO

Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.


Assuntos
Histona Desmetilases , Leucemia Mieloide Aguda , Humanos , Diferenciação Celular/genética , Cromatina/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Histona Desmetilases/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Nucleic Acids Res ; 50(17): 9797-9813, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36095118

RESUMO

Chromatin complexes control a vast number of epigenetic developmental processes. Filamentous fungi present an important clade of microbes with poor understanding of underlying epigenetic mechanisms. Here, we describe a chromatin binding complex in the fungus Aspergillus nidulans composing of a H3K4 histone demethylase KdmB, a cohesin acetyltransferase (EcoA), a histone deacetylase (RpdA) and a histone reader/E3 ligase protein (SntB). In vitro and in vivo evidence demonstrate that this KERS complex is assembled from the EcoA-KdmB and SntB-RpdA heterodimers. KdmB and SntB play opposing roles in regulating the cellular levels and stability of EcoA, as KdmB prevents SntB-mediated degradation of EcoA. The KERS complex is recruited to transcription initiation start sites at active core promoters exerting promoter-specific transcriptional effects. Interestingly, deletion of any one of the KERS subunits results in a common negative effect on morphogenesis and production of secondary metabolites, molecules important for niche securement in filamentous fungi. Consequently, the entire mycotoxin sterigmatocystin gene cluster is downregulated and asexual development is reduced in the four KERS mutants. The elucidation of the recruitment of epigenetic regulators to chromatin via the KERS complex provides the first mechanistic, chromatin-based understanding of how development is connected with small molecule synthesis in fungi.


Assuntos
Aspergillus nidulans , Cromatina , Acetiltransferases/metabolismo , Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Cromatina/genética , Cromatina/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Genes Fúngicos , Genes Reguladores , Histona Desacetilases/metabolismo , Histona Desmetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Esterigmatocistina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
14.
Toxicol Ind Health ; 38(11): 745-756, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36120900

RESUMO

C/EBP-homologous protein (CHOP) and histone H3 lysine 4 (H3K4) methylation have been verified to be correlated with apoptosis, whereas their biological function in arsenic-induced hepatocyte apoptosis through the mitochondrial pathway is still unclear. This study aimed to explore the specific regulatory mechanism of CHOP and H3K4me1/2 in arsenic-induced mitochondrial apoptosis in hepatocytes. Apoptosis and proliferation results showed arsenic promoted apoptosis and inhibited cell growth in BRL-3A cells. Meanwhile, arsenic treatment significantly upregulated the 78-kDa glucose-regulated protein (GRP78), CHOP, su(var)-3-9,enhancer-of-zeste,trithorax (SET) domain containing 7/9 (SET7/9), H3K4me1/2, BIM and BAX expression, while markedly downregulated lysine-specific histone demethylase 1 (LSD1) and BCL2 expression. After down-regulating CHOP, LSD1, and (su(var)-3-9,enhancer-of-zeste,trithorax) domain-containing protein 7/9 (SET7/9) in BRL-3A cells by siRNA, silencing CHOP and SET7/9 notably attenuated the pro-apoptotic and anti-proliferative effects of arsenic treatment on BRL-3A cells, which was reversed after inhibiting LSD1. In addition, our results suggested that knockdown of CHOP altered the expression of mitochondrial-associated proteins BCL2 and BIM, whereas knockdown of LSD1 and SET7/8 regulated the level of H3K4me1/2 modification and BAX protein. Coupled with chromatin immunoprecipitation results, we found that the level of CHOP in the promoter regions of BCL2 and BIM was significantly increased in BRL-3A cells exposed to 30 µmol/L NaAsO2 for 24 h, whereas the levels of H3K4me1/2 in the promoter regions of BAX were unchanged. Collectively, these data indicated that arsenic triggered the mitochondrial pathway to induce hepatocyte apoptosis by up-regulating the levels of CHOP and H3K4me1/2.


Assuntos
Arsênio , Histonas , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Metilação , Histonas/metabolismo , Lisina/metabolismo , Arsênio/toxicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Apoptose , Hepatócitos/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo
15.
Diabetes ; 71(12): 2513-2529, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36162056

RESUMO

The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates nonalcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting that LSD1 has a context-dependent role in promoting maladaptive changes in obesity. In analysis of insulin target tissues we identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Lisina/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Insulina/metabolismo , Histona Desmetilases/metabolismo , Inflamação/metabolismo , Lipídeos , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Fígado/metabolismo
16.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36142158

RESUMO

Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)-a negative KDM5C target-and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Cromatina/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Hipóxia/genética , Interleucina-6/metabolismo , Lisina/metabolismo , Oxigênio/metabolismo , Survivina/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral/genética
17.
Metallomics ; 14(9)2022 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-36073756

RESUMO

A series of cyclometalated iridium(III) complexes with the formula [Ir(C^N)2 L](PF6) (C^N = 2-phenylpyridine (ppy, in Ir-1), 2-(2-thienyl)pyridine (thpy, in Ir-2), 2-(2,4-difluorophenyl)pyridine (dfppy, in Ir-3), L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol) were designed and synthesized, which utilize 8-hydroxyquinoline derivative as N^N ligands to chelate the cofactor Fe2+ of the Jumonji domain-containing protein (JMJD) histone demethylase. As expected, the results of UV/Vis titration analysis confirm the chelating capabilities of Ir-1-3 for Fe2+, and molecular docking studies also show that Ir-1-3 can interact with the active pocket of JMJD protein, and treatment of cells with Ir-1-3 results in significant upregulation of trimethylated histone 3 lysine 9 (H3K9Me3), indicating the inhibition of JMJD activity. Meanwhile, Ir-1-3 exhibit much higher cytotoxicity against the tested tumor cell lines compared with the clinical chemotherapeutic agent cisplatin. And Ir-1-3 can block the cell cycle at the G2/M phase and inhibit cell migration and colony formation. Further studies show that Ir-1-3 can specifically accumulate in lysosomes, damage the integrity of lysosomes, and induce apoptosis and autophagy. Reduction of mitochondrial membrane potential and elevation of reactive oxygen species also contribute to the antitumor effects of Ir-1-3. Finally, Ir-1 can inhibit tumor growth effectively in vivo and increase the expression of H3K9Me3 in tumor tissues. Our study demonstrates that these iridium(III) complexes are promising anticancer agents with multiple functions, including the inhibition of JMJD and induction of apoptosis and autophagy.


Assuntos
Antineoplásicos , Complexos de Coordenação , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose , Autofagia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Histona Desmetilases/metabolismo , Histona Desmetilases/farmacologia , Histonas , Irídio/farmacologia , Ligantes , Lisina/farmacologia , Lisossomos/metabolismo , Simulação de Acoplamento Molecular , Oxiquinolina/farmacologia , Piridinas , Espécies Reativas de Oxigênio/metabolismo
18.
Clin Cancer Res ; 28(20): 4551-4564, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-35920742

RESUMO

PURPOSE: The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically "cold" tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with (i) decreased neuroendocrine characteristics and (ii) activation of NOTCH signaling. We previously showed that inhibition of the lysine-specific demethylase 1a (LSD1) demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD-1 inhibition in SCLC. EXPERIMENTAL DESIGN: We employed a syngeneic immunocompetent model of SCLC, derived from a genetically engineered mouse model harboring Rb1/Trp53 inactivation, to investigate combining the LSD1 inhibitor bomedemstat with anti-PD-1 therapy. In vivo experiments were complemented by cell-based studies in murine and human models. RESULTS: Bomedemstat potentiated responses to PD-1 inhibition in a syngeneic model of SCLC, resulting in increased CD8+ T-cell infiltration and strong tumor growth inhibition. Bomedemstat increased MHC class I expression in mouse SCLC tumor cells in vivo and augmented MHC-I induction by IFNγ and increased killing by tumor-specific T cells in cell culture. CONCLUSIONS: LSD1 inhibition increased MHC-I expression and enhanced responses to PD-1 inhibition in vivo, supporting a new clinical trial to combine bomedemstat with standard-of-care PD-1 axis inhibition in SCLC.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Animais , Morte Celular , Inibidores Enzimáticos/uso terapêutico , Etoposídeo/uso terapêutico , Histona Desmetilases/metabolismo , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/patologia , Lisina/uso terapêutico , Camundongos , Platina/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/patologia , Microambiente Tumoral
19.
Nat Commun ; 13(1): 4998, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36008402

RESUMO

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine "inflammatory" phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.


Assuntos
Fator 1 de Resposta a Butirato/metabolismo , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/metabolismo
20.
Int J Mol Sci ; 23(16)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36012577

RESUMO

BACKGROUND: Lysine demethylase 4C (KDM4C) is a nuclear protein that is essential for histone modification and acts as an important regulator of several transcription factors. Previous studies have shown that KDM4C may also play a role in mediating stress responses. The purpose of this study was to examine the roles of KDM4C in kidney development and acute kidney injury (AKI). METHODS: The effect of KDM4C on kidney development was assessed by comparing the kidney phenotype between 96 zebrafish embryos treated with kdm4c-morpholino oligonucleotide and 96 untreated zebrafish embryos. We further examined whether KDM4C is essential for maintaining cell survival in AKI. Cultured human renal tubular cells were used for the in vitro study. Wild-type and Kdm4c knockout mice (C57BL/6NTac-Kdm4ctm1a(KOMP)Wtsi) were divided into a sham group and model group, and then subjected to ischemic reperfusion kidney injury (IRI-AKI). Blood samples and kidneys were collected at different time points (day 3, day 7, day 14, and day 28) and were processed for in vivo studies (n = 8 in each group). RESULTS: Kdm4c knockdown significantly decreased zebrafish embryo survival and impaired kidney development. The in vitro study showed that KDM4C inhibition by JIB04 significantly increased cellular apoptosis under oxidative stress conditions. KDM4C knockdown cells had impaired autophagy function under stress conditions. The IRI-AKI mice study showed that KDM4C protein levels dynamically changed and were significantly correlated with HIF-1α levels in AKI. Kdm4c-/- mice had significantly more severe renal impairment and increased kidney fibrosis than the wild-type mice. Cytokine array results also indicated that the kidneys of Kdm4c-/- mice had increased inflammation in AKI compared with the wild-type mice. Further RNA sequence analysis revealed that KDM4C may regulate transcription factors related to mitochondrial dynamics and function. CONCLUSIONS: Our study suggests that KDM4C may play a critical role in regulating mitochondria, which is related to a protective effect on maintaining cell survival in AKI.


Assuntos
Injúria Renal Aguda , Histona Desmetilases com o Domínio Jumonji , Traumatismo por Reperfusão , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Animais , Apoptose , Histona Desmetilases/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra
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