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1.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201047

RESUMO

MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation. MYC deregulation in tumors leads to its pervasive genome-wide binding of both promoters and distal regulatory regions, associated with selective transcriptional control of a large fraction of cellular genes. This pairs with alterations of cell cycle control which drive anticipated S-phase entry and reshape the DNA-replication landscape. Under these circumstances, the fine tuning of DNA replication and transcription becomes critical and may pose an intrinsic liability in MYC-overexpressing cancer cells. Here, we will review the current understanding of how MYC controls DNA and RNA synthesis, discuss evidence of replicative and transcriptional stress induced by MYC and summarize preclinical data supporting the therapeutic potential of triggering replicative stress in MYC-driven tumors.


Assuntos
Replicação do DNA , Regulação da Expressão Gênica , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Dano ao DNA , Humanos , Neoplasias/genética , Neoplasias/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198626

RESUMO

Human stem-cell factor (hSCF) stimulates the survival, proliferation, and differentiation of hematopoietic cells by binding to the c-Kit receptor. Various applications of hSCF require the efficient and reliable production of hSCF. hSCF exists in three forms: as two membrane-spanning proteins hSCF248 and hSCF229 and truncated soluble N-terminal protein hSCF164. hSCF164 is known to be insoluble when expressed in Escherichia coli cytoplasm, requiring a complex refolding procedure. The activity of hSCF248 has never been studied. Here, we investigated novel production methods for recombinant hSCF164 and hSCF248 without the refolding process. To increase the solubility of hSCF164, maltose-binding protein (MBP) and protein disulfide isomerase b'a' domain (PDIb'a') tags were attached to the N-terminus of hSCF164. These fusion proteins were overexpressed in soluble form in the Origami 2(DE3) E. coli strain. These solubilization effects were enhanced at a low temperature. His-hSCF248, the poly-His tagged form of hSCF248, was expressed in a highly soluble form without a solubilization tag protein, which was unexpected because His-hSCF248 contains a transmembrane domain. hSCF164 was purified using affinity and ion-exchange chromatography, and His-hSCF248 was purified by ion-exchange and gel filtration chromatography. The purified proteins stimulated the proliferation of TF-1 cells. Interestingly, the EC50 value of His-hSCF248 was 1 pg/mL, 100-fold lower than 9 ng/mL hSCF164. Additionally, His-hSCF248 decreased the doubling time, increased the proportion of S and G2/M stages in the cell cycle, and increased the c-Myc expression at a 1000-fold lower concentration than hSCF164. In conclusion, His-hSCF248 was expressed in a soluble form in E. coli and had stronger activity than hSCF164. The molecular chaperone, MBP, enabled the soluble overexpression of hSCF164.


Assuntos
Fator de Células-Tronco/biossíntese , Sequência de Aminoácidos , Ciclo Celular , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Plasmídeos/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Solubilidade , Fator de Células-Tronco/química
3.
Yi Chuan ; 43(6): 601-614, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284990

RESUMO

C-Myc gene is aberrantly highly expressed and participates in cancer initiation and development in various malignant tumors including esophageal cancer, while the underlying mechanism(s) still remains unclear. In order to explore the role of c-Myc in the occurrence of esophageal cancer, we successfully established the esophageal organoids (EOs) as the research model. By constructing a lentivirus overexpressing c-Myc and developing more effective infection method, EOs with stable overexpression of c-Myc were efficiently obtained. The morphologies of EOs with or without overexpressing c-Myc were first analyzed with ImageJ, which showed no difference between two groups during continuous subculture. Subsequently, we applied immunofluorescence and CCK8 assays to evaluate the cell proliferation, and the results showed no change in the c-Myc-overexpressed group as compared to control EOs. Furthermore, qPCR was used to detect the expression of genes that are related to cell cycle, cell metabolism as well as esophageal cancer. The results indicated the expression of these genes was not significantly increased in the c-Myc overexpressing EOs. In conclude, we discovered that overexpression of c-Myc gene alone in the esophagus organoid is not sufficient to induce carcinogenesis in esophageal carcinoma. In this study, we successfully established an esophagus organoid culture system and together with efficient lentivirus-infection method for investigation on the effects of overexpressing c-Myc in esophageal cancer. Our work demonstrated a promising research model for the study of esophagus development and esophageal cancer.


Assuntos
Neoplasias Esofágicas , Organoides , Proliferação de Células , Neoplasias Esofágicas/genética , Humanos , Proteínas Proto-Oncogênicas c-myc/genética
4.
Nat Commun ; 12(1): 3094, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035273

RESUMO

Short-term, systemic expression of the Yamanaka reprogramming factors (Oct-3/4, Sox2, Klf4 and c-Myc [OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo. However, the mechanisms by which OSKM promotes tissue regeneration are unknown. In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice. In contrast, expressing OSKM directly in SCs does not improve muscle regeneration. Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates Wnt4. This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence. Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche.


Assuntos
Diferenciação Celular/genética , Reprogramação Celular/genética , Miofibrilas/metabolismo , Regeneração/genética , Células Satélites de Músculo Esquelético/metabolismo , Nicho de Células-Tronco , Animais , Células Cultivadas , Feminino , Expressão Gênica , Fatores de Transcrição Kruppel-Like/genética , Camundongos Transgênicos , Miofibrilas/fisiologia , Fator 3 de Transcrição de Octâmero/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição SOXB1/genética , Células Satélites de Músculo Esquelético/citologia , Proteína Wnt4/genética
5.
J Med Chem ; 64(11): 7261-7271, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34043360

RESUMO

After extensive screening of aerospace compounds in an effort to source a novel anticancer agent, RRx-001, a first-in-class dinitroazetidine small molecule, was selected for advancement into preclinical and clinical development. RRx-001 is a minimally toxic small molecule with a distinct chemical structure and mechanism of action. The paradox of RRx-001 is that it mediates both antitumor cytotoxicity and normal tissue protection. The question of exactly how RRx-001 does this, and by means of what mechanism(s), depending on the route of delivery, intravenous or intratumoral, are explored. RRx-001 is currently in phase 2 and 3 clinical trials for the treatment of multiple solid tumor malignancies and as a supportive care drug.


Assuntos
Antineoplásicos/química , Azetidinas/química , Antígeno CD47/metabolismo , Nitrocompostos/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Antígeno CD47/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Meia-Vida , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Nitrocompostos/farmacologia , Nitrocompostos/uso terapêutico , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-myc/genética , Relação Estrutura-Atividade , Transplante Heterólogo , Macrófagos Associados a Tumor/citologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo
6.
J Med Chem ; 64(10): 6720-6729, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33961424

RESUMO

As c-MYC is one of the central players in triple-negative breast cancer (TNBC) oncogenesis, inhibiting c-MYC expression would be an effective anticancer strategy. Transcription-induced negative supercoiling is crucial in the regulation of c-MYC transcription, which facilitates the formation of a G4 structure in NHE III1 that can silence the transcription. However, topoisomerase 1 (Topo1) can dissipate this negative supercoiling, leading to continuous activation of c-MYC transcription. Thus, dual ligands targeting both Topo1 and c-MYC G4 appear to be significant in cancer therapy. In this study, a series of new dibenzoquinoxaline derivatives were designed, synthesized, and evaluated for both Topo1 and c-MYC inhibition. Among them, 5 was identified as the most promising dual ligand, which could effectively inhibit Topo1 activity and strongly stabilize c-MYC G4, thereby inhibiting cancer cell growth. Accordingly, this work suggests that this dual-targeting strategy may be effective in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/química , Quadruplex G/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Quinoxalinas/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Desenho de Fármacos , Feminino , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Transplante Heterólogo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
7.
Nucleic Acids Res ; 49(10): 5943-5955, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33999211

RESUMO

DNA binding proteins recognize DNA specifically or non-specifically using direct and indirect readout mechanisms like sliding, hopping, and diffusion. However, a common difficulty in explicitly elucidating any particular mechanism of site-specific DNA-protein recognition is the lack of knowledge regarding target sequences and inadequate account of non-specific interactions, in general. Here, we decipher the structural basis of target search performed by the key regulator of expression of c-myc proto-oncogene, the human RBMS1 protein. In this study, we have shown the structural reorganization of this multi-domain protein required for recognizing the specific c-myc promoter sequence. The results suggest that a synergy between structural re-organization and thermodynamics is necessary for the recognition of target sequences. The study presents another perspective of looking at the DNA-protein interactions.


Assuntos
Proteínas de Ligação a DNA/química , Genes myc , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas de Ligação a RNA/química , Sítios de Ligação , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Proteínas de Ligação a DNA/genética , Expressão Gênica , Humanos , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Domínios Proteicos , Proteínas de Ligação a RNA/genética , Proteínas Recombinantes , Termodinâmica
8.
Nat Commun ; 12(1): 2625, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976171

RESUMO

CRISPR-based active genetic elements, or gene-drives, copied via homology-directed repair (HDR) in the germline, are transmitted to progeny at super-Mendelian frequencies. Active genetic elements also can generate widespread somatic mutations, but the genetic basis for such phenotypes remains uncertain. It is generally assumed that such somatic mutations are generated by non-homologous end-joining (NHEJ), the predominant double stranded break repair pathway active in somatic cells. Here, we develop CopyCatcher systems in Drosophila to detect and quantify somatic gene conversion (SGC) events. CopyCatchers inserted into two independent genetic loci reveal unexpectedly high rates of SGC in the Drosophila eye and thoracic epidermis. Focused RNAi-based genetic screens identify several unanticipated loci altering SGC efficiency, one of which (c-MYC), when downregulated, promotes SGC mediated by both plasmid and homologous chromosome-templates in human HEK293T cells. Collectively, these studies suggest that CopyCatchers can serve as effective discovery platforms to inform potential gene therapy strategies.


Assuntos
Sistemas CRISPR-Cas/genética , Reparo do DNA por Junção de Extremidades , Conversão Gênica , Edição de Genes/métodos , Reparo de DNA por Recombinação , Animais , Animais Geneticamente Modificados , Drosophila/genética , Estudos de Viabilidade , Feminino , Loci Gênicos , Terapia Genética/métodos , Células HEK293 , Humanos , Masculino , Modelos Animais , Proteínas Proto-Oncogênicas c-myc/genética
9.
Gene ; 791: 145718, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33991650

RESUMO

The incidence rates of colorectal cancer have been increasing in the last decades, yet the overall survival rate is still not ideal. There is a need to further investigate detailed mechanism for colorectal cancer tumorigenesis. The biological function of protein arginine methyltransferases 3 (PRMT3) is seldom studied in tumorigenesis. Here, we attempted to elucidate the link between PRMT3 and tumorigenesis in colorectal cancer. Results revealed that PRMT3 was upregulated in colorectal cancer. Besides, PRMT3 overexpression promoted colorectal cancer cell proliferation, migration, and invasion. Regarding mechanism for colorectal cancer tumorigenesis, PRMT3 stabilized C-MYC and the pro-tumorigenesis function of PRMT3 was dependent on C-MYC. Clinically, these findings might provide a novel therapeutical treatment strategy for colorectal cancer.


Assuntos
Neoplasias Colorretais/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Metilação , Invasividade Neoplásica/genética , Proteína-Arginina N-Metiltransferases/fisiologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Ribossômicas/metabolismo
10.
Nucleic Acids Res ; 49(10): 5905-5915, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33978746

RESUMO

DNA G-Quadruplexes (G4s) formed in oncogene promoters regulate transcription. The oncogene MYC promoter G4 (MycG4) is the most prevalent G4 in human cancers. However, the most studied MycG4 sequence bears a mutated 3'-residue crucial for ligand recognition. Here, we report a new drug-like small molecule PEQ without a large aromatic moiety that specifically binds MycG4. We determined the NMR solution structures of the wild-type MycG4 and its 2:1 PEQ complex, as well as the structure of the 2:1 PEQ complex of the widely used mutant MycG4. Comparison of the two complex structures demonstrates specific molecular recognition of MycG4 and shows the clear effect of the critical 3'-mutation on the drug binding interface. We performed a systematic analysis of the four available complex structures involving the same mutant MycG4, which can be considered a model system for parallel G4s, and revealed for the first time that the flexible flanking residues are recruited in a conserved and sequence-specific way, as well as unused potential for selective ligand-G4 hydrogen-bond interactions. Our results provide the true molecular basis for MycG4-targeting drugs and new critical insights into future rational design of drugs targeting MycG4 and parallel G4s that are prevalent in promoter and RNA G4s.


Assuntos
Quadruplex G , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/química , Quinolinas/química , Sítios de Ligação , Dicroísmo Circular , Humanos , Ligação de Hidrogênio , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Terapia de Alvo Molecular , Mutação , Proteínas Proto-Oncogênicas c-myc/genética , Espectrometria de Fluorescência
11.
Zhonghua Xue Ye Xue Za Zhi ; 42(2): 124-128, 2021 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-33858042

RESUMO

Objective: To investigate the incidence of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement in Chinese diffuse large B-cell lymphoma (DLBCL) . Methods: From January 2013 to August 2020, 922 DLBCL cases were collected. C-MYC and BCL2 protein expression levels were analyzed by immunohistochemistry staining. Fluorescence in situ hybridization was used to detect the structural abnormalities of MYC, BCL2, and BCL6, including gene breaks and copy number changes. Results: MYC and BCL2 and/or BCL6 gene breaks were found in 29 out of 922 DLBCL cases (3.15%) , including 25 cases of double-hit lymphoma (DHL; 14 cases involving MYC and BCL2 rearrangements and 11 cases involving MYC and BCL6 rearrangements) and four cases involving MYC, BCL2, and BCL6 rearrangements, referring to triple-hit lymphoma. According to the threshold of C-MYC ≥40% and BCL2 ≥50%, 541 cases (58.68%) overexpressed C-MYC and BCL2 proteins, including 22 DHL cases. Moreover, according to the threshold of C-MYC ≥70% and BCL2 ≥50%, 52 cases (5.64%) overexpressed C-MYC and BCL2 proteins, including nine DHL cases. The P53 protein expression was detected by immunohistochemistry staining. The mutant P53 expression pattern was shown in 101 out of 709 cases (14.25%) , whereas 13 cases (1.83%) were negative, likely indicating P53 gene fragment deletion. Conclusion: The incidence of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements was low in DLBCLs, and no significant correlation between gene abnormality and protein overexpression was shown. The correct diagnosis of DHL depends on molecular genetic detection.


Assuntos
Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-myc , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Incidência , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética
12.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799592

RESUMO

B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature can be attributed to both proteins playing essential roles in the normal functioning of a cell, and by extension a whole organism, but also due to their central role in disease, most notably, cancer. Many cancers arise due to genetic lesions resulting in deregulation of both proteins, and indeed the development and survival of tumours is often dependent on co-operativity between these protein families. In this review we will discuss the individual roles of both proteins in cancer, describe cancers where co-operativity between them has been well-characterised and finally, some strategies to target these proteins therapeutically.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Compostos de Anilina/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Compostos de Bifenilo/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaios Clínicos como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Morfolinos/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Nitrofenóis/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/uso terapêutico , Rituximab/uso terapêutico , Transdução de Sinais , Sulfonamidas/uso terapêutico
13.
Mol Cell ; 81(7): 1365-1367, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798412

RESUMO

Ciesla et al. (2021) uncover intricate circuits of post-transcriptional regulation induced by the Myc oncogene, including alternative splicing and translational control, which are relevant for breast cancer prognosis and contribute to metabolic reprogramming and stem cell-like features of cancer cells.


Assuntos
Neoplasias da Mama , Carcinogênese/genética , Humanos , Poder Psicológico , Proteínas Proto-Oncogênicas c-myc/genética , RNA , Spliceossomos
14.
Life Sci ; 277: 119438, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33798549

RESUMO

AIMS: Immune checkpoints regulate immunity to prevent autoimmunity and protect the host from damage during pathogenic infection. They also participate in subverting immune surveillance and promote antitumor immunity in cancers. Although immunotherapy improves clinical outcomes, not all cancer patients experience expected responses after therapy. Hence, it would be meaningful to explore crucial immune checkpoints in cancers for future immunotherapies. METHODS AND KEY FINDINGS: By analyzing pan-cancer data in The Cancer Genome Atlas (TCGA), cluster of differentiation 276 (CD276), also known as B7H3, was found to be a risk gene in several cancers. A positive correlation existed between CD276 and natural killer (NK) cell infiltration. Overexpression of CD276 attenuated NK cell-mediated cell killing. Furthermore, CD276 levels showed a significant negative association with microRNA (miR)-29c-3p. Overexpression of miR-29c-3p rescued CD276-reduced NK cell cytotoxicity. According to gene set enrichment analyses, CD276-associated genes were found to be enriched in genes that targeted Myc. A negative correlation existed between miR-29 expression and Myc activity. CD276 enhanced Myc phosphorylation levels while suppressing miR-29c-3p expression. In contrast, miR-29c-3p inhibited CD276 expression, leading to reduced Myc activity. Myc suppressed miR-29c-3p expression while promoting CD276 upregulation. SIGNIFICANCE: These findings suggest that a negative regulatory loop among CD276, Myc, and miR-29c-3p influences cancer cells against NK cell cytotoxicity.


Assuntos
Antígenos B7/metabolismo , Citotoxicidade Imunológica/imunologia , Regulação Neoplásica da Expressão Gênica , Células Matadoras Naturais/imunologia , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Apoptose , Antígenos B7/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Humanos , MicroRNAs/genética , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Células Tumorais Cultivadas
15.
Toxicol Appl Pharmacol ; 421: 115536, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33865896

RESUMO

Cadmium (Cd) can induce ovarian injury by microRNAs (miRNAs), however, the molecular mechanism of miRNAs after Cd exposure have not known. In this study, 56-day-old adult female Sprague-Dawley (SD) rats were injection with PMSG, after 48 h, ovarian granulosa cells (GCs) were extracted and cultured for 24 h, then treated with 0, 2.5, 5, 10 and 20 µM Cd for 24 h. The results showed that expression levels of miR-92a-2-5p (upregulated) and Bcl2 (downregulated) changed significantly after Cd exposure. The messenger RNA (mRNA) and protein expression levels of DNMT1, DNMT3A, and DNMT3B had changed, but no obvious differences were found in miR-92a-2-5p single site methylation. The transcription factors C-MYC (upregulated), E2F1 (downregulated), and SP1 (downregulated), which target miRNAs significantly changed after exposure to Cd. The human ovarian GC tumor line (COV434) was used to knocked down C-myc, and the expression of miR-92a-2-5p was downregulated in the COV434-C-myc + 10 µM Cd group compared with COV434 cells. The N6-methyladenosine (m6A) methylation modification levels of long noncoding RNA (lncRNA) MT1JP and lncRNA CDKN2B-AS, which regulate miR-92a-2-5p were detected. In the 10 µM Cd group, m6A methylation levels at MT1JP-84, CDKN2B-AS-257, and CDKN2B-AS-329 were reduced. In summary, after Cd exposure, expression of miR-92a-2-5p, which targets the antiapoptotic gene Bcl2, was upregulated, which may be primarily related to upregulation of C-myc. MiR-92a-2-5p promoter DNA methylation may has no obvious effect on miR-92a-2-5p. Otherwise, the role of m6A methylation modified lncRNA MT1JP and lncRNA CDKN2B-AS in the regulation of miR-92a-2-5p needs further study.


Assuntos
Cloreto de Cádmio/toxicidade , Células da Granulosa/efeitos dos fármacos , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transcrição Genética/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/metabolismo , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Feminino , Células da Granulosa/metabolismo , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , MicroRNAs/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos Sprague-Dawley , Regulação para Cima
16.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801599

RESUMO

MYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ativação Transcricional , Animais , Apoptose , Carcinogênese , Diferenciação Celular , Proliferação de Células , Cromatina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Epigênese Genética , Epigenoma , Genoma Humano , Células-Tronco Hematopoéticas/citologia , Homeostase , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Leucemia/metabolismo , Linfoma/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo
17.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801762

RESUMO

Origin recognition complex (ORC) binds to replication origins in eukaryotic DNAs and plays an important role in replication. Although yeast ORC is known to sequence-specifically bind to a replication origin, how human ORC recognizes a replication origin remains unknown. Previous genome-wide studies revealed that guanine (G)-rich sequences, potentially forming G-quadruplex (G4) structures, are present in most replication origins in human cells. We previously suggested that the region comprising residues 413-511 of human ORC subunit 1, hORC1413-511, binds preferentially to G-rich DNAs, which form a G4 structure in the absence of hORC1413-511. Here, we investigated the interaction of hORC1413-511 with various G-rich DNAs derived from human c-myc promoter and telomere regions. Fluorescence anisotropy revealed that hORC1413-511 binds preferentially to DNAs that have G4 structures over ones having double-stranded structures. Importantly, circular dichroism (CD) and nuclear magnetic resonance (NMR) showed that those G-rich DNAs retain the G4 structures even after binding with hORC1413-511. NMR chemical shift perturbation analyses revealed that the external G-tetrad planes of the G4 structures are the primary binding sites for hORC1413-511. The present study suggests that human ORC1 may recognize replication origins through the G4 structure.


Assuntos
DNA/genética , Quadruplex G , Complexo de Reconhecimento de Origem , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética , Telômero/ultraestrutura , Sítios de Ligação , Replicação do DNA , Polarização de Fluorescência , Humanos , Espectroscopia de Ressonância Magnética , Fases de Leitura Aberta , Complexo de Reconhecimento de Origem/genética , Ligação Proteica , Origem de Replicação
18.
Cancer Med ; 10(9): 3139-3152, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33818013

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignant disease worldwide. Although the diagnosis and treatment of HCC have greatly improved in the recent years, there is still a lack of accurate methods to predict the prognosis of patients. Evidence has shown that Hippo signaling in tissues adjacent to HCC plays a significant role in HCC development. In the present study, we aimed to construct a model based on the expression of Hippo-related genes (HRGs) in tissues adjacent to HCC to predict the prognosis of HCC patients. METHODS: Gene expression data of paired normal tissues adjacent to HCC (PNTAH) and clinical information were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The HRG signature was constructed using four canonical Hippo-related pathways. Univariate Cox regression analysis was used to screen survival-related HRGs. LASSO and multivariate Cox regression analyses were used to construct the prognostic model. The true and false positive rates of the model were confirmed using receiver operating characteristic (ROC) analysis. RESULTS: The prognostic model was constructed based on the expression levels of five HRGs (NF2, MYC, BIRC3, CSNK1E, and MINK1) in PNTAH. The mortality rate of HCC patients increased as the risk score determined by the model increased. Furthermore, the risk score was found to be an independent risk factor for the survival of patients. ROC analysis showed that the prognostic model had a better predictive value than the other conventional clinical parameters. Moreover, the reliability of the prognostic model was confirmed in TCGA-LIHC cohort. A nomogram was generated to predict patient survival. An exploration of the predictive value of the model in HCC tissues indicated that the model is PNTAH-specific. CONCLUSIONS: We developed and validated a prognostic model based on the expression levels of five HRGs in PNTAH, and this model should be helpful in predicting the prognosis of patients with HCC.


Assuntos
Carcinoma Hepatocelular/genética , Expressão Gênica , Neoplasias Hepáticas/genética , Fígado , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína 3 com Repetições IAP de Baculovírus/genética , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Caseína Quinase Iépsilon/genética , Caseína Quinase Iépsilon/metabolismo , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Nomogramas , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Curva ROC , Fatores de Risco , Transcriptoma , Adulto Jovem
19.
FEBS Lett ; 595(12): 1639-1655, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33914337

RESUMO

MXDs are transcription repressors that antagonize MYC-mediated gene activation. MYC, when associated with MIZ1, acts also as a repressor of a subset of genes, including p15 and p21. A role for MXDs in regulation of MYC-repressed genes is not known. We report that MXDs activate transcription of p15 and p21 in U2OS cells. This activation required DNA binding by MXDs and their interaction with MIZ1. MXD mutants deficient in MIZ1 binding interacted with the MYC-binding partner MAX and were active as repressors of MYC-activated genes but failed to activate MYC-repressed genes. Mutant MXDs with reduced DNA-binding affinity interacted with MAX and MIZ1 but neither repressed nor activated transcription. Our data show that MXDs and MYC have a reciprocally antagonistic potential to regulate transcription of target genes.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Regulação da Expressão Gênica , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Células HEK293 , Humanos , Fatores de Transcrição Kruppel-Like/genética , Proteínas Proto-Oncogênicas c-myc/genética
20.
J Med Chem ; 64(9): 5654-5666, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33881857

RESUMO

The discovery of novel bioactive lipids that promote human health is of great importance. Combining "suspect" and targeted lipidomic liquid chromatography-high-resolution mass spectrometry (LC-HRMS) approaches, a previously unrecognized class of oxidized fatty acids, the saturated oxo fatty acids (SOFAs), which carry the oxo functionality at various positions of the long chain, was identified in human plasma. A library of SOFAs was constructed, applying a simple green photochemical hydroacylation reaction as the key synthetic step. The synthesized SOFAs were studied for their ability to inhibit in vitro the cell growth of three human cancer cell lines. Four oxostearic acids (OSAs) were identified to inhibit the cell growth of human lung carcinoma A549 cells. 6OSA and 7OSA exhibited the highest cell growth inhibitory potency, suppressing the expression of both STAT3 and c-myc, which are critical regulators of cell growth and proliferation. Thus, naturally occurring SOFAs may play a role in the protection of human health.


Assuntos
Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/química , Lipídeos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Humanos , Lipídeos/química , Espectrometria de Massas , Oxirredução , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ácidos Esteáricos/análise , Ácidos Esteáricos/metabolismo , Ácidos Esteáricos/farmacologia
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