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1.
Int J Biol Sci ; 20(12): 4691-4712, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39309447

RESUMO

B-Myb, also known as MYB proto-oncogene like 2 (MYBL2), is an important transcription factor implicated in transcription regulation, cell cycle and tumorigenesis. However, the molecular mechanism underlying B-Myb-controlled transactivation in different cell contexts as well as its functional implication in cancers remains elusive. In this study, we have conducted a comprehensive genome-wide analysis of B-Myb binding sites in multiple immortalized or cancer cell lines and identified its critical target genes. The results revealed that B-Myb regulates a common set of core cell cycle genes and cell type-specific genes through collaboration with other important transcription factors (e.g. NFY and MuvB complex) and binding to cell type-invariant promoters and cell type-specific enhancers and super-enhancers. KIF2C, UBE2C and MYC were further validated as B-Myb target genes. Loss-of-function analysis demonstrated that KIF2C knockdown inhibited tumor cell growth both in vitro and in vivo, suppressed cell motility and cell cycle progression, accompanied with defects in microtubule organization and mitosis, strongly suggesting that KIF2C is a critical regulator of cancer cell growth and mitosis, and maintains high cancer cell motility ability and microtubule dynamics. Pan-cancer transcriptomic analysis revealed that the overexpression of both B-Myb and KIF2C presents as independent prognostic markers in various types of cancer. Notably, B-Myb associates with NFYB, binds to target gene promoters, enhancers and super-enhancers, and provokes a cascade of oncogenic gene expression profiles in cancers. Overall, our results highly suggest the critical implication of B-Myb-mediated gene regulation in cancers, and the promising therapeutic and prognostic potentials of B-Myb and KIF2C for cancer diagnosis and treatment.


Assuntos
Ativação Transcricional , Humanos , Ativação Transcricional/genética , Linhagem Celular Tumoral , Neoplasias/genética , Neoplasias/metabolismo , Proto-Oncogene Mas , Regulação Neoplásica da Expressão Gênica , Cinesinas/metabolismo , Cinesinas/genética , Transativadores/metabolismo , Transativadores/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Camundongos , Estudo de Associação Genômica Ampla , Regiões Promotoras Genéticas , Movimento Celular/genética
2.
Int J Biol Macromol ; 270(Pt 1): 132244, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729459

RESUMO

To combat cancer, a comprehensive understanding of the molecular mechanisms and behaviors involved in carcinogenesis is crucial, as tumorigenesis is a complex process influenced by various genetic events and disease hallmarks. The B-MYB gene encodes a transcription factor involved in cell cycle regulation, survival, and differentiation in normal cells. B-MYB can be transformed into an oncogene through mutations, and abnormal expression of B-MYB has been identified in various cancers, including lung cancer, and is associated with poor prognosis. Targeting this oncogene is a promising approach for anti-cancer drug design. B-MYB has been deemed undruggable in previous reports, necessitating the search for novel therapeutic options. In this study, we found that the B-MYB gene promoter contains several G/C rich motifs compatible with G-quadruplex (G4) formation. We investigated and validated the existence of G4 structures in the promoter region of B-MYB, first in vitro using a combination of bioinformatics, biophysical, and biochemical methods, then in cell with the recently developed G4access method.


Assuntos
Quadruplex G , Regiões Promotoras Genéticas , Proto-Oncogene Mas , Regiões Promotoras Genéticas/genética , Humanos , Transativadores/genética , Transativadores/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Motivos de Nucleotídeos/genética
3.
Sci Rep ; 14(1): 7733, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565963

RESUMO

B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Animais , Camundongos , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular Imunogênica , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Apoptose
4.
Int J Biol Macromol ; 266(Pt 1): 131055, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38522681

RESUMO

The B-MYB gene encodes a transcription factor (B-MYB) that regulates cell growth and survival. Abnormal expression of B-MYB is frequently observed in lung cancer and poses challenges for targeted drug therapy. Oncogenes often contain DNA structures called G-quadruplexes (G4s) in their promoter regions, and B-MYB is no exception. These G4s play roles in genetic regulation and are potential cancer treatment targets. In this study, a probe was designed to specifically identify a G4 within the promoter region of the B-MYB gene. This probe combines an acridine derivative ligand with a DNA segment complementary to the target sequence, enabling it to hybridize with the adjacent sequence of the G4 being investigated. Biophysical studies demonstrated that the acridine derivative ligands C5NH2 and C8NH2 not only effectively stabilized the G4 structure but also exhibited moderate affinity. They were capable of altering the G4 topology and exhibited enhanced fluorescence emission in the presence of this quadruplex. Additionally, these ligands increased the number of G4s observed in cellular studies. Through various biophysical studies, the target sequence was shown to form a G4 structure, even with an extra nucleotide tail added to its flanking region. Cellular studies confirmed the co-localization between the target sequence and the developed probe.


Assuntos
Proteínas de Ciclo Celular , Corantes Fluorescentes , Quadruplex G , Humanos , Corantes Fluorescentes/química , Regiões Promotoras Genéticas , Proto-Oncogene Mas , Ligantes , Transativadores/genética , Transativadores/metabolismo , Transativadores/química , Acridinas/química , Acridinas/farmacologia
5.
Photodiagnosis Photodyn Ther ; 42: 103558, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37030434

RESUMO

OBJECTIVE: Photodynamic therapy (PDT) may be an effective therapeutic strategy for colorectal cancer at an early stage. However, malignant cells' resistance to photodynamic agents can lead to treatment failure. MYBL2 (B-Myb) is an oncogene in colorectal carcinogenesis and development, for which little research has focused on its effect on drug resistance. MATERIALS AND METHODS: In the present work, a colorectal cancer cell line with a stable knockdown of MYBL2 (ShB-Myb) was constructed first. Chlorin e6 (Ce6) was utilized to induced PDT. The anti-cancer efficacy was measured by CCK-8, PI staining, and Western blots. The drug uptake of Ce6 was assayed by flow cytometry and confocal microscopy. The ROS generation was detected by the CellROX probe. DDSB and DNA damage were assayed through comet experiment and Western blots. The over-expression of MYBL2 was conducted by MYBL2 plasmid. RESULTS: The findings indicated that the viability of ShB-Myb treated with Ce6-PDT was not decreased compared to control SW480 cells (ShNC), which were resistant to PDT. Further investigation revealed reduced photosensitizer enrichment and mitigated oxidative DNA damage in colorectal cancer cells with depressed MYBL2. It turned out that SW480 cells knocking down MYBL2 showed phosphorylation of NF-κB and led to up-regulation of ABCG2 expression thereupon. When MYBL2 was replenished back in MYBL2-deficient colorectal cancer cells, phosphorylation of NF-κB was blocked and ABCG2 expression up-regulation was suppressed. Additionally, replenishment of MYBL2 also increased the enrichment of Ce6 and the efficacy of PDT. CONCLUSION: In summary, MYBL2 absence in colorectal cancer contributes to drug resistance by activating NF-κB to up-regulate ABCG2 and thereby leading to photosensitizer Ce6 efflux. This study provides a novel theoretical basis and strategy for how to effectively improve the anti-tumor efficacy of PDT.


Assuntos
Clorofilídeos , Neoplasias Colorretais , Fotoquimioterapia , Porfirinas , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fotoquimioterapia/métodos , Regulação para Cima , NF-kappa B/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Porfirinas/farmacologia , Linhagem Celular Tumoral , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Neoplasias , Transativadores/metabolismo , Proteínas de Ciclo Celular/metabolismo
6.
Chem Biol Interact ; 374: 110412, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36812959

RESUMO

Currently, resistance to oxaliplatin (OXA) has become an important obstacle to improving the clinical outcome of patients with colorectal cancer (CRC). Moreover, long non-coding RNAs (lncRNAs) have been documented in cancer chemoresistance, and our bioinformatic analysis suggested an involvement of lncRNA CCAT1 in CRC development. In this context, this study aimed to clarify the upstream and downstream mechanisms underpinning the effect of CCAT1 in the resistance of CRC to OXA. The expression of CCAT1 and the upstream B-MYB in the CRC samples was predicted by bioinformatics analysis and then verified using RT-qPCR in CRC cell lines. Accordingly, overexpression of B-MYB and CCAT1 was observed in CRC cells. SW480 cell line was used for the construction of OXA-resistant cell line (SW480R). Ectopic expression and knockdown experiments of B-MYB and CCAT1 were conducted in SW480R cells to delineate their roles in the malignant phenotypes and half-maximal (50%) inhibitory concentration (IC50) of OXA. It was found that CCAT1 promoted the resistance of CRC cells to OXA. Mechanistically, B-MYB transcriptionally activated CCAT1, which recruited DNMT1 to inhibit SOCS3 expression through elevating the SOCS3 promoter methylation. By this mechanism, the resistance of CRC cells to OXA was enhanced. Meanwhile, these in vitro findings were reproduced in vivo on xenografts of SW480R cells in nude mice. To sum up, B-MYB might promote the chemoresistance of CRC cells to OXA via regulating the CCAT1/DNMT1/SOCS3 axis.


Assuntos
Neoplasias Colorretais , RNA Longo não Codificante , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Oxaliplatina/farmacologia , RNA Longo não Codificante/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Fatores de Transcrição/metabolismo
7.
Trends Biochem Sci ; 47(12): 1009-1022, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35835684

RESUMO

Cell cycle-dependent gene transcription is tightly controlled by the retinoblastoma (RB):E2F and DREAM complexes, which repress all cell cycle genes during quiescence. Cyclin-dependent kinase (CDK) phosphorylation of RB and DREAM allows for the expression of two gene sets. The first set of genes, with peak expression in G1/S, is activated by E2F transcription factors (TFs) and is required for DNA synthesis. The second set, with maximum expression during G2/M, is required for mitosis and is coordinated by the MuvB complex, together with B-MYB and Forkhead box M1 (FOXM1). In this review, we summarize the key findings that established the distinct control mechanisms regulating G1/S and G2/M gene expression in mammals and discuss recent advances in the understanding of the temporal control of these genes.


Assuntos
Proteínas de Ciclo Celular , Proteínas Repressoras , Animais , Proteínas Repressoras/genética , Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Mitose , Quinases Ciclina-Dependentes/genética , Expressão Gênica , Mamíferos
8.
Int J Biol Sci ; 18(10): 4151-4170, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844795

RESUMO

Lung adenocarcinoma (LUAD) causes severe cancer death worldwide. E2F2 is a canonical transcription factor implicated in transcription regulation, cell cycle and tumorigenesis. The role of E2F2 as well as its transcription regulatory network in LUAD remains obscure. In this study, we constructed a weighted gene co-expression network and identified several key modules and networks overrepresented in LUAD, including the E2F2-centered transcription regulatory network. Function analysis revealed that E2F2 overexpression accelerated cell growth, cell cycle progression and cell motility in LUAD cells whereas E2F2 knockdown inhibited these malignant phenotypes. Mechanistic investigations uncovered various E2F2-regulated downstream genes and oncogenic signaling pathways. Notably, three core transcription factors of E2F2, B-Myb and FOXM1 from the LUAD transcription regulatory network exhibited positive expression correlation, associated with each other, mutually transactivated each other, and regulated similar downstream gene cascades, hence constituting a consolidated core transcription regulatory circuitry. Moreover, E2F2 could promote and was essentially required for LUAD growth in orthotopic mouse models. Prognosis modeling revealed that a two-gene signature of E2F2 and PLK1 from the transcription regulatory circuitry remarkably stratified patients into low- and high-risk groups. Collectively, our results clarified the critical roles of E2F2 and the exquisite core transcription regulatory circuitry of E2F2/B-Myb/FOXM1 in LUAD progression.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Fator de Transcrição E2F2/metabolismo , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Regulação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Fatores de Transcrição/metabolismo
9.
Acta Clin Croat ; 60(1): 16-24, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34588717

RESUMO

Breast cancer is the most common malignancy in females. Despite its well-established prognostic factors, our prognostic ability at an individual patient level remains limited. In this study, the immunohistochemical expression of B-Myb and DNA topoisomerase 2-alpha (Topo2a) was analyzed in primary tumors to identify patients with a higher risk of disease recurrence after adjuvant chemotherapy for early invasive breast cancer. We analyzed a cohort of 215 early invasive breast cancer patients having undergone surgery from 2002 to 2003 at the Zagreb University Hospital Centre, including 153 patients treated with adjuvant chemotherapy. All of them were followed-up prospectively for at least ten years according to routine institutional practice. Statistically significant correlations were found between B-Myb and Topo2a expression levels and particular well-established prognostic factors. B-Myb expression was lower in estrogen receptor (ER)-positive tumors (p=0.0773), whereas larger tumors and those with positive lymphovascular invasion displayed a statistically significantly higher B-Myb expression (p=0.0409 and p=0.0196). Higher tumor grade indicated higher Topo2a values (p=0.0102 and p=0.0069). The subgroup with the expression of both proteins above the median value had an almost statistically significantly (p=0.0613) inferior prognosis compared to the rest of the cohort. Study results showed the B-Myb and Topo2a expression to have a prognostic value in breast cancer patients after adjuvant chemotherapy, which should be additionally explored in future studies in a larger patient cohort.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , DNA Topoisomerases Tipo II/uso terapêutico , Feminino , Humanos , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2
10.
Annu Rev Genet ; 55: 309-329, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34496610

RESUMO

Perfectly orchestrated periodic gene expression during cell cycle progression is essential for maintaining genome integrity and ensuring that cell proliferation can be stopped by environmental signals. Genetic and proteomic studies during the past two decades revealed remarkable evolutionary conservation of the key mechanisms that control cell cycle-regulated gene expression, including multisubunit DNA-binding DREAM complexes. DREAM complexes containing a retinoblastoma family member, an E2F transcription factor and its dimerization partner, and five proteins related to products of Caenorhabditis elegans multivulva (Muv) class B genes lin-9, lin-37, lin-52, lin-53, and lin-54 (comprising the MuvB core) have been described in diverse organisms, from worms to humans. This review summarizes the current knowledge of the structure, function, and regulation of DREAM complexes in different organisms, as well as the role of DREAM in human disease.


Assuntos
Proteínas de Caenorhabditis elegans , Proteômica , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas Repressoras/genética
11.
Biochem Biophys Res Commun ; 573: 19-26, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34375765

RESUMO

As a common treatment of human glioma, ionizing radiation (IR) was reported to result in cell cycle arrest. However, the mechanisms underlying IR-induced abnormal cell cycle remain largely unclear. Here we found that IR caused an elevated expression of B-Myb and cell cycle-related proteins, as well as G2/M phase arrest in U251 cells instead of U87 cells. However, the knockdown of B-Myb by small interfering RNAs ameliorated the increasing of cell cycle-related proteins and G2/M phase arrest induced by IR. Further analysis demonstrated that decreased-B-Myb enhanced the sensitivity of U251 cells to IR. Moreover, the establishment of H1299 cell line proved that B-Myb expression was associated with the status of p53. Immunoprecipitation (IP) and chromatin immunoprecipitation (CHIP) assay results indicated that mutant p53 and SP1 regulated the expression of B-Myb via different mechanisms. This study not only elucidated the role of B-Myb in IR-induced cell cycle alternation, but also provided insight into mechanism of B-Myb expression.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Glioma/metabolismo , Radiação Ionizante , Transativadores/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Glioma/patologia , Humanos , Células Tumorais Cultivadas
12.
EMBO Rep ; 22(5): e51120, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33779025

RESUMO

Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR-dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be different due to alterations in cell cycle phase length. The transcription factor MYBL2, which is implicated in cell cycle regulation, is expressed a hundred to a thousand-fold more in ESCs compared with somatic cells. Here we show that MYBL2 activates ATM and suppresses replication stress in ESCs. Consequently, loss of MYBL2 or inhibition of ATM or Mre11 in ESCs results in replication fork slowing, increased fork stalling and elevated origin firing. Additionally, we demonstrate that inhibition of CDC7 activity rescues replication stress induced by MYBL2 loss and ATM inhibition, suggesting that uncontrolled new origin firing may underlie the replication stress phenotype resulting from loss/inhibition of MYBL2 and ATM. Overall, our study proposes that in addition to ATR, a MYBL2-MRN-ATM replication stress response pathway functions in ESCs to control DNA replication initiation and prevent genome instability.


Assuntos
Proteínas de Ciclo Celular , Células-Tronco Pluripotentes , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Replicação do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Pluripotentes/metabolismo
13.
Oncol Lett ; 21(2): 166, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33552284

RESUMO

B-Myb is a critical transcription factor in regulating cell cycle. Dysregulated expression of B-Myb promotes tumor formation and development. B-Myb is a proto-oncogene ubiquitously expressed in proliferating cells, which maintains normal cell cycle progression. It participates in cell apoptosis, tumorigenesis and aging. In addition, B-Myb is overexpressed in several malignant tumors, including breast cancer, lung cancer and hepatocellular carcinoma, and is associated with tumor development. B-Myb expression is also associated with the prognosis of patients with malignant tumors. Both microRNAs and E2F family of transcription factors (E2Fs) contribute to the function of B-Myb. The present review highlights the association between B-Myb and malignant tumors, and offers a theoretical reference for the diagnosis and treatment of malignant tumors.

14.
FEBS Lett ; 594(24): 4266-4279, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32979888

RESUMO

The transcription factor B-MYB is an important regulator of cell cycle-related processes that is activated by step-wise phosphorylation of multiple sites by cyclin-dependent kinases (CDKs) and conformational changes induced by the peptidylprolyl cis/trans isomerase Pin1. Here, we show that a conserved amino acid sequence around Ser-577 in the C-terminal part of B-MYB is able to interact with the B-MYB DNA-binding domain. Phosphorylation of Ser-577 disrupts this interaction and is regulated by the interplay of CDKs and the phosphatase CDC14B. Deletion of sequences surrounding Ser-577 hyperactivates the transactivation potential of B-MYB, decreases its proteolytic stability, and causes cell cycle defects. Overall, we show for the first time that B-MYB can undergo an intramolecular interaction that is controlled by the phosphorylation state of Ser-577.


Assuntos
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Fosfosserina/metabolismo , Serina/metabolismo , Transativadores/química , Transativadores/metabolismo , Sequência de Aminoácidos , Animais , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Quinases Ciclina-Dependentes/metabolismo , DNA/genética , DNA/metabolismo , Fosfatases de Especificidade Dupla/metabolismo , Células HEK293 , Humanos , Fosforilação , Ligação Proteica/genética , Domínios Proteicos/genética , Proteólise , Serina/genética , Transativadores/genética , Ativação Transcricional/genética
15.
Biochim Biophys Acta Rev Cancer ; 1874(2): 188407, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32853735

RESUMO

The MYBL2 gene, also known as B-MYB, is essential to regulate vital cellular processes including cell proliferation, differentiation and DNA repair. Changes in these pathways can facilitate cancer development and as such targeting these processes represent an effective method to treat multiple cancer types. Alterations in gene expression have been identified in cancer cells including changes in MYBL2, which appears to be of particular significance in breast cancer (BC) patients. Upregulation of MYBL2 in BC can occur via multiple mechanisms, including changes in regulation by micro RNAs, amplification of the 20q13 gene coding region and single nucleotide polymorphisms in the MYBL2 gene itself or associated genes. Evidence from multiple studies suggests MYBL2 expression could be used as a biomarker for disease severity in BC patients, which could identify those who require a more targeted treatment approach to prevent disease recurrence. In fact, high MYBL2 expression correlates with BC metastasis, worse relapse free survival and shorter overall survival, providing strong evidence that upregulation of MYBL2 functions contributes to more aggressive disease. This review summarises the significance of amplified MYBL2 expression to the development and pathogenesis of BC and suggests ways to target this multifunctional protein as an effective treatment to prevent disease recurrence.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Amplificação de Genes , Transativadores/genética , Regulação para Cima , Biomarcadores Tumorais/genética , Feminino , Regulação da Expressão Gênica , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise de Sobrevida
16.
Exp Cell Res ; 389(1): 111889, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32032602

RESUMO

The copy number of mitochondrial DNA (mtDNA) is decreased in most cancer types, including hepatocellular carcinoma (HCC), compared to normal counterparts. However, a decrease in mtDNA usually leads to defects in cell proliferation, which contradicts the robustness of cancer cell proliferation. In this study, we found that four out of seven HCC cell lines were of the mtDNA-less type. Interestingly, FOXM1, a member of the FOX transcription factor family, was highly expressed in a subset of them with proliferative potential maintained. B-MYB, a partner of FOXM1, was also expressed in the same cell lines. RNAi-mediated experiments demonstrated that when FOXM1/B-MYB was silenced in the cell lines, cell cycle-related genes were downregulated, while p21Cip1 was induced with senescence-associated ß-galactosidase, resulting in G1/S cell cycle arrest. These results suggest that high expression of FOXM1/B-MYB is critical for sustaining cell proliferation in mtDNA-less cells. In addition, we found that high expression of FOXM1 was mediated by the deubiquitinating enzyme, OTUB1, in one cell line. Thus, interference with FOXM1/B-MYB expression, such as through OTUB1 inhibition, may induce a dormant state of senescence-like proliferation arrest in mtDNA-less cancer cells. This finding may be utilized for the development of precision medicine for relevant cancers.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , DNA Mitocondrial/genética , Proteína Forkhead Box M1/genética , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Cultivadas , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/patologia , Regulação para Cima/genética
17.
Mol Cell Oncol ; 7(1): 1682924, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31993496

RESUMO

Deciphering principles of inter-tumoral heterogeneity is crucial for refinement of precision oncology. We have recently demonstrated that 'oncogenic cooperation' between somatic mutations and regulatory germline variants can serve as a major cause for inter-tumoral heterogeneity, suggesting the requirement of integrating the regulatory genome into 'omics'-based precision oncology.

18.
Mol Cell Oncol ; 6(6): e1648026, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692816

RESUMO

The Hippo pathway plays a major role in regulating organ size during embryogenesis. Loss of Hippo signaling can cause cancer due to unrestricted cell proliferation. Recently we found that Yes-associated protein 1 (YAP1), the major downstream effector of Hippo, promotes mitotic gene expression and proliferation through binding and activating the Myb-MuvB (MMB) complex subunit MYB proto-oncogene like 2 (B-MYB).

19.
Acta Pharmacol Sin ; 40(11): 1394-1403, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31444477

RESUMO

Cathepsin L (CTSL), a cysteine protease, is responsible for the degradation of a variety of proteins. It is known to participate in neuronal apoptosis associated with abnormal cell cycle. However, the mechanisms underlying CTSL-induced cell apoptosis remain largely unclear. We reported here that rotenone caused an activation of CTSL expression in PC-12 cells, while knockdown of CTSL by small interfering RNAs or its inhibitor reduced the rotenone-induced cell cycle arrest and apoptosis. Moreover, elevation of CTSL and increased-apoptosis were accompanied by induction of B-Myb, a crucial cell cycle regulator. We found that B-Myb was increased in rotenone-treated PC-12 cells and knockdown of B-Myb ameliorated rotenone-stimulated cell apoptosis. Further analysis demonstrated that CTSL influenced the expression of B-Myb as suppression of CTSL activity led to a decreased B-Myb expression, whereas overexpression of CTSL resulted in B-Myb induction. Reduction of B-Myb in CTSL-overexpressing cells revealed that regulation of cell cycle-related proteins, including cyclin A and cyclin B1, through CTSL was mediated by the transcription factor B-Myb. In addition, we demonstrated that the B-Myb target, Bim, and its regulator, Egr-1, which was also associated with CTSL closely, were both involved in rotenone-induced apoptosis in PC-12 cells. Our data not only revealed the role of CTSL in rotenone-induced neuronal apoptosis, but also indicated the involvement of B-Myb in CTSL-related cell cycle regulation.


Assuntos
Apoptose/fisiologia , Catepsina L/fisiologia , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/metabolismo , Ciclo Celular/fisiologia , Ciclina A/metabolismo , Ciclina B1/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Células PC12 , Ratos , Rotenona/farmacologia
20.
Cell Rep ; 27(12): 3533-3546.e7, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216474

RESUMO

YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma de Pulmão/patologia , Proteínas de Ciclo Celular/metabolismo , Ciclo Celular , Cromatina/metabolismo , Regulação da Expressão Gênica , Mitose/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Mama/citologia , Mama/metabolismo , Proteínas de Ciclo Celular/genética , Células Cultivadas , Cromatina/genética , Elementos Facilitadores Genéticos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Prognóstico , Regiões Promotoras Genéticas , Taxa de Sobrevida , Transativadores/genética , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
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