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1.
Front Oncol ; 10: 560487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262941

RESUMO

Evidence for research over the past decade shows that epigenetic regulation mechanisms run through the development and prognosis of tumors. Therefore, small molecular compounds targeting epigenetic regulation have become a research hotspot in the development of cancer therapeutic drugs. According to the obvious abnormality of histone acetylation when tumors occur, it suggests that histone acetylation modification plays an important role in the process of tumorigenesis. Currently, as a new potential anti-cancer therapeutic drugs, many active small molecules that target histone acetylation regulatory enzymes or proteins such as histone deacetylases (HDACs), histone acetyltransferase (HATs) and bromodomains (BRDs) have been developed to restore abnormal histone acetylation levels to normal. In this review, we will focus on summarizing the changes of histone acetylation levels during tumorigenesis, as well as the possible pharmacological mechanisms of small molecules that target histone acetylation in cancer treatment.

2.
Front Oncol ; 10: 585288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194731

RESUMO

One common and reversible type of post-translational modification (PTM) is the addition of O-linked ß-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), and its dynamic balance is controlled by O-GlcNAc transferase (OGT) and glycoside hydrolase O-GlcNAcase (OGA) through the addition or removal of O-GlcNAc groups. A large amount of research data confirms that proteins regulated by O-GlcNAcylation play a pivotal role in cells. In particularly, imbalanced levels of OGT and O-GlcNAcylation have been found in various types of cancers. Recently, increasing evidence shows that imbalanced O-GlcNAcylation directly or indirectly impacts the process of cancer metastasis. This review summarizes the current understanding of the influence of O-GlcNAc-proteins on the regulation of cancer metastasis. It will provide a theoretical basis to further elucidate of the molecular mechanisms underlying cancer emergence and progression.

3.
Front Pharmacol ; 10: 9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837865

RESUMO

Coptis, a traditional medicinal plant, has been used widely in the field of traditional Chinese medicine for many years. More recently, the chemical composition and bioactivity of Coptis have been studied worldwide. Berberine is a main component of Rhizoma Coptidis. Modern medicine has confirmed that berberine has pharmacological activities, such as anti-inflammatory, analgesic, antimicrobial, hypolipidemic, and blood pressure-lowering effects. Importantly, the active ingredient of berberine has clear inhibitory effects on various cancers, including colorectal cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, and cervical cancer. Cancer, ranked as one of the world's five major incurable diseases by WHO, is a serious threat to the quality of human life. Here, we try to outline how berberine exerts antitumor effects through the regulation of different molecular pathways. In addition, the berberine-mediated regulation of epigenetic mechanisms that may be associated with the prevention of malignant tumors is described. Thus, this review provides a theoretical basis for the biological functions of berberine and its further use in the clinical treatment of cancer.

4.
Protein Cell ; 8(10): 713-723, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28488246

RESUMO

Dynamic changes of the post-translational O-GlcNAc modification (O-GlcNAcylation) are controlled by O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and the glycoside hydrolase O-GlcNAcase (OGA) in cells. O-GlcNAcylation often occurs on serine (Ser) and threonine (Thr) residues of the specific substrate proteins via the addition of O-GlcNAc group by OGT. It has been known that O-GlcNAcylation is not only involved in many fundamental cellular processes, but also plays an important role in cancer development through various mechanisms. Recently, accumulating data reveal that O-GlcNAcylation at histones or non-histone proteins can lead to the start of the subsequent biological processes, suggesting that O-GlcNAcylation as 'protein code' or 'histone code' may provide recognition platforms or executive instructions for subsequent recruitment of proteins to carry out the specific functions. In this review, we summarize the interaction of O-GlcNAcylation and epigenetic changes, introduce recent research findings that link crosstalk between O-GlcNAcylation and epigenetic changes, and speculate on the potential coordination role of O-GlcNAcylation with epigenetic changes in intracellular biological processes.


Assuntos
Acetilglucosamina/metabolismo , Epigênese Genética , Processamento de Proteína Pós-Traducional , Animais , Glicosídeo Hidrolases/metabolismo , Humanos , N-Acetilglucosaminiltransferases/metabolismo , Neoplasias/genética , Neoplasias/metabolismo
5.
J Biol Chem ; 292(24): 10014-10025, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28450392

RESUMO

The human males absent on the first (MOF)-containing histone acetyltransferase nonspecific lethal (NSL) complex comprises nine subunits including the O-linked N-acetylglucosamine (O-GlcNAc) transferase, isoform 1 (OGT1). However, whether the O-GlcNAc transferase activity of OGT1 controls histone acetyltransferase activity of the NSL complex and whether OGT1 physically interacts with the other NSL complex subunits remain unclear. Here, we demonstrate that OGT1 regulates the activity of the NSL complex by mainly acetylating histone H4 Lys-16, Lys-5, and Lys-8 via O-GlcNAcylation and stabilization of the NSL complex subunit NSL3. Knocking down or overexpressing OGT1 in human cells remarkably affected the global acetylation of histone H4 residues Lys-16, Lys-5, and Lys-8. Because OGT1 is a subunit of the NSL complex, we also investigated the function of OGT1 in this complex. Co-transfection/co-immunoprecipitation experiments combined with in vitro O-GlcNAc transferase assays confirmed that OGT1 specifically binds to and O-GlcNAcylates NSL3. In addition, wheat germ agglutinin affinity purification verified the occurrence of O-GlcNAc modification on NSL3 in cells. Moreover, O-GlcNAcylation of NSL3 by wild-type OGT1 (OGT1-WT) stabilized NSL3. This stabilization was lost after co-transfection of NSL3 with an OGT1 mutant, OGT1C964A, that lacks O-GlcNAc transferase activity. Furthermore, stabilization of NSL3 by OGT1-WT significantly increased the global acetylation levels of H4 Lys-5, Lys-8, and Lys-16 in cells. These results suggest that OGT1 regulates the activity of the NSL complex by stabilizing NSL3.


Assuntos
Histona Acetiltransferases/metabolismo , Histonas/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Acetilação , Substituição de Aminoácidos , Animais , Células HEK293 , Células HeLa , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/química , Histona Acetiltransferases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/química , N-Acetilglucosaminiltransferases/genética , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Proteínas Nucleares/genética , Mutação Puntual , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estabilidade Proteica , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Interferência de RNA , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Células Sf9 , Spodoptera , Especificidade por Substrato
6.
PLoS One ; 10(10): e0141014, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26473953

RESUMO

Histone post-translational modification heritably regulates gene expression involved in most cellular biological processes. Experimental studies suggest that alteration of histone modifications affects gene expression by changing chromatin structure, causing various cellular responses to environmental influences. Arsenic (As), a naturally occurring element and environmental pollutant, is an established human carcinogen. Recently, increasing evidence suggests that As-mediated epigenetic mechanisms may be involved in its toxicity and carcinogenicity, but how this occurs is still unclear. Here we present evidence that suggests As-induced global histone H4K16 acetylation (H4K16ac) partly due to the direct physical interaction between As and histone acetyltransferase (HAT) hMOF (human male absent on first) protein, leading to the loss of hMOF HAT activity. Our data show that decreased global H4K16ac and increased deacetyltransferase HDAC4 expression occurred in arsenic trioxide (As2O3)-exposed HeLa or HEK293T cells. However, depletion of HDAC4 did not affect global H4K16ac, and it could not raise H4K16ac in cells exposed to As2O3, suggesting that HDAC4 might not directly be involved in histone H4K16 de-acetylation. Using As-immobilized agarose, we confirmed that As binds directly to hMOF, and that this interaction was competitively inhibited by free As2O3. Also, the direct interaction of As and C2CH zinc finger peptide was verified by MAIDI-TOF mass and UV absorption. In an in vitro HAT assay, As2O3 directly inhibited hMOF activity. hMOF over-expression not only increased resistance to As and caused less toxicity, but also effectively reversed reduced H4K16ac caused by As exposure. These data suggest a theoretical basis for elucidating the mechanism of As toxicity.


Assuntos
Arsenicais/metabolismo , Histona Acetiltransferases/metabolismo , Histonas/química , Histonas/metabolismo , Lisina/metabolismo , Óxidos/metabolismo , Óxidos/toxicidade , Acetilação/efeitos dos fármacos , Trióxido de Arsênio , Morte Celular/efeitos dos fármacos , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Células HEK293 , Células HeLa , Histona Acetiltransferases/química , Humanos , Ligação Proteica , Dedos de Zinco
7.
PLoS Genet ; 9(11): e1003940, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24244196

RESUMO

hMOF (MYST1), a histone acetyltransferase (HAT), forms at least two distinct multiprotein complexes in human cells. The male specific lethal (MSL) HAT complex plays a key role in dosage compensation in Drosophila and is responsible for histone H4K16ac in vivo. We and others previously described a second hMOF-containing HAT complex, the non-specific lethal (NSL) HAT complex. The NSL complex has a broader substrate specificity, can acetylate H4 on K16, K5, and K8. The WD (tryptophan-aspartate) repeat domain 5 (WDR5) and host cell factor 1 (HCF1) are shared among members of the MLL/SET (mixed-lineage leukemia/set-domain containing) family of histone H3K4 methyltransferase complexes. The presence of these shared subunits raises the possibility that there are functional links between these complexes and the histone modifications they catalyze; however, the degree to which NSL and MLL/SET influence one another's activities remains unclear. Here, we present evidence from biochemical assays and knockdown/overexpression approaches arguing that the NSL HAT promotes histone H3K4me2 by MLL/SET complexes by an acetylation-dependent mechanism. In genomic experiments, we identified a set of genes including ANKRD2, that are affected by knockdown of both NSL and MLL/SET subunits, suggested they are co-regulated by NSL and MLL/SET complexes. In ChIP assays, we observe that depletion of the NSL subunits hMOF or NSL1 resulted in a significant reduction of both H4K16ac and H3K4me2 in the vicinity of the ANKRD2 transcriptional start site proximal region. However, depletion of RbBP5 (a core component of MLL/SET complexes) only reduced H3K4me2 marks, but not H4K16ac in the same region of ANKRD2, consistent with the idea that NSL acts upstream of MLL/SET to regulate H3K4me2 at certain promoters, suggesting coordination between NSL and MLL/SET complexes is involved in transcriptional regulation of certain genes. Taken together, our results suggest a crosstalk between the NSL and MLL/SET complexes in cells.


Assuntos
Histona Acetiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , Complexos Multiproteicos/genética , Proteína de Leucina Linfoide-Mieloide/genética , Animais , Células HEK293 , Histona Acetiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Metilação , Complexos Multiproteicos/isolamento & purificação , Complexos Multiproteicos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Estrutura Terciária de Proteína , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Especificidade por Substrato
8.
PLoS One ; 8(5): e62014, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23671581

RESUMO

Hypoxia-inducible factor 1α (HIF1α) is an important cellular survival protein under hypoxic conditions, regulating the cellular response to low oxygen tension via recruitment of a transcriptional co-activator, p300/CBP. p300/CBP induces expression of multiple genes involved in cell survival, proliferation, angiogenesis, and tumor development. Thus, a strategy to inhibit hypoxic responses in tumors may be to target the protein-protein interaction between HIF1α and p300/CBP. Here, we document, for the first time, that the aminocoumarin antibiotic, novobiocin, directly blocks the protein-protein interaction between the HIF1α C-terminal activation domain (CTAD) and the cysteine-histidine rich (CH1) region of p300/CBP. Also, novobiocin down-regulated HIF1α-controlled gene expression, specifically CA9, which is related to tumorigenesis. In a monolayer cell culture, novobiocin inhibited cell proliferation and colony formation in the MCF-7 human breast adenocarcinoma cell line and the A549 human lung cancer cell line. Rescue experiments revealed that the recombinant CTAD fragment of HIF1α partially reversed novobiocin's inhibitory effects on cell proliferation and colony formation in MCF-7 cells. These findings suggest a novel mechanism of action for novobiocin which has the potential for innovative therapeutic use in tumor treatment.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Proteína p300 Associada a E1A/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Novobiocina/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteína p300 Associada a E1A/química , Proteína p300 Associada a E1A/isolamento & purificação , Células HEK293 , Células HeLa , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/isolamento & purificação , Células MCF-7 , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , Ligação Proteica/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas , Ativação Transcricional/efeitos dos fármacos
9.
J Exp Clin Cancer Res ; 32: 8, 2013 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-23394073

RESUMO

BACKGROUND: MYST1 (also known as hMOF), a member of the MYST family of histone acetyltransferases (HATs) as an epigenetic mark of active genes, is mainly responsible for histone H4K16 acetylation in the cells. Recent studies have shown that the abnormal gene expression of hMOF is involved in certain primary cancers. Here we examined the involvement of hMOF expression and histone H4K16 acetylation in primary renal cell carcinoma (RCC). Simultaneously, we investigated the correlation between the expression of hMOF and clear cell RCC (ccRCC) biomarker carbohydrase IX (CA9) in RCC. MATERIALS AND METHODS: The frozen RCC tissues and RCC cell lines as materials, the reverse transcription polymerase chain reaction (RT-PCR), western blotting and immunohistochemical staining approaches were used. RESULTS: RT-PCR results indicate that hMOF gene expression levels frequently downregulated in 90.5% of patients (19/21) with RCC. The reduction of hMOF protein in both RCC tissues and RCC cell lines is tightly correlated with acetylation of histone H4K16. In addition, overexpression of CA9 was detected in 100% of ccRCC patients (21/21). However, transient transfection of hMOF in ccRCC 786-0 cells did not affect both the gene and protein expression of CA9. CONCLUSION: hMOF as an acetyltransferase of H4K16 might be involved in the pathogenesis of kidney cancer, and this epigenetic changes might be a new CA9-independent RCC diagnostic maker.


Assuntos
Carcinoma de Células Renais/enzimologia , Histona Acetiltransferases/genética , Neoplasias Renais/enzimologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Carcinoma de Células Renais/genética , Regulação para Baixo , Epigênese Genética , Epigenômica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Histona Acetiltransferases/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
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