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1.
Mol Cell ; 83(20): 3679-3691.e8, 2023 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-37797621

RESUMO

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.


Assuntos
Neoplasias , Proteínas Supressoras de Tumor , Humanos , Proteínas Supressoras de Tumor/metabolismo , Proteína BRCA1/metabolismo , Ubiquitinação , Histonas/genética , Histonas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Reparo de DNA por Recombinação , DNA , Reparo do DNA
2.
Cancer Sci ; 113(8): 2560-2574, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35574707

RESUMO

Histone deacetylases (HDACs) are involved in many processes including tumor cell growth and proliferation and regulation of gene expression. To clarify the role of class IIa HDACs in the metastasis of colon adenocarcinoma, we used the class IIa HDAC inhibitor TMP269 and found that it effectively inhibited the migration ability of colon adenocarcinoma cells. Next, we silenced the member of class IIa HDACs and confirmed that the migratory ability of colon adenocarcinoma cells was significantly inhibited by silencing HDAC5 or HDAC7. HDAC5 plays a variety of roles in human cancers. Here, we examined the role of HDAC5 in colon adenocarcinoma. The results indicated that HDAC5 was highly expressed in tumor tissues and negatively correlated with the expression of miR-148a-3p. Moreover, the expression of HDAC5 was correlated with tumor progression. HDAC5 markedly increased the invasion and migration of cancer cells in vitro, an effect that could be inhibited by overexpression of miR-148a-3p. Following an intraperitoneal injection of colon adenocarcinoma cells in athymic nude mice, HDAC5 promoted tumor implant. Together, these findings showed that HDAC5 overexpression in colon adenocarcinoma is consistent with tumor progression and tumor cell migration and the impact of HDAC5 overexpression is reduced by miR-148a-3p.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Histona Desacetilases , MicroRNAs , Adenocarcinoma/genética , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética
3.
BMC Cancer ; 22(1): 1038, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195841

RESUMO

BACKGROUND: The incidence of colorectal cancer (CRC) is considered to be the third-highest malignant tumor among all carcinomas. The alterations in cellular bioenergetics (metabolic reprogramming) are associated with several malignant phenotypes in CRC, such as tumor cell proliferation, invasion, metastasis, chemotherapy resistance, as well as promotes its immune escape. However, the expression pattern of metabolism-associated genes that mediate metabolic reprogramming in CRC remains unknown. METHODS: In this study, we screened out CPT2 by investigating the function of a series of metabolism-related genes in CRC progression by integrating the data from the TCGA and GEO databases. Next, we collected CRC tissues (n = 24) and adjacent non-tumor tissues (n = 8) and analyzed mRNA levels by qRT-PCR, and proteins levels of CPT2 in CRC cell lines by western blotting. CCK-8 assay, colony formation assay, Edu assay and flow cytometry assay were performed to assess the effects of CPT2 on proliferation in vitro. RESULTS: We identified 236 metabolism-related genes that are differentially expressed in colorectal cancer, of which 49 up-regulated and 187 down-regulated, and found CPT2 as the most significant gene associated with favorable prognosis in CRC. It was revealed that CPT2 expression was consistently down-regulated in CRC cell lines and tissues. Moreover, knockdown of CPT2 could promote the proliferative ability of CRC cells, whereas over-expression of CPT2 significantly suppressed the cell growth. CONCLUSION: In summary, CPT2 can provide new insights about the progression and occurrence of the tumor as it acts as an independent prognostic factor in CRC sufferers.


Assuntos
Neoplasias Colorretais , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , RNA Mensageiro
4.
Signal Transduct Target Ther ; 7(1): 87, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35351858

RESUMO

Oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), but an estimated 50% of patients will eventually stop responding to treatment due to acquired resistance. This study revealed that diminished MEIS1 expression was detected in CRC and harmed the survival of CRC patients. MEIS1 impaired CRC cell viabilities and tumor growth in mice and enhanced CRC cell sensitivity to oxaliplatin by preventing DNA damage repair. Mechanistically, oxaliplatin resistance following MEIS1 suppression was critically dependent on enhanced FEN1 expression. Subsequently, we confirmed that EZH2-DNMT3a was assisted by lncRNA ELFN1-AS1 in locating the promoter of MEIS1 to suppress MEIS1 transcription epigenetically. Based on the above, therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance. This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance, based on their controlling of MEIS1 expression, which deserve further verification as a prospective therapeutic strategy.


Assuntos
Neoplasias Colorretais , Animais , Carcinogênese/genética , Proliferação de Células/genética , Transformação Celular Neoplásica , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Camundongos , Oxaliplatina/farmacologia
5.
Front Cell Dev Biol ; 9: 671211, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178996

RESUMO

The dysregulation of transcriptional factors (TFs) leads to malignant growth and the development of colorectal cancer (CRC). Herein, we sought to identify the transcription factors relevant to the prognosis of colorectal cancer patients. We found 526 differentially expressed TFs using the TCGA database of colorectal cancer patients (n = 544) for the differential analysis of TFs (n = 1,665) with 210 upregulated genes as well as 316 downregulated genes. Subsequently, GO analysis and KEGG pathway analysis were performed for these differential genes for investigating their pathways and function. At the same time, we established a genetic risk scoring model for predicting the overall survival (OS) by using the mRNA expression levels of these differentially regulated TFs, and defined the CRC into low and high-risk categories which showed significant survival differences. The genetic risk scoring model included four high-risk genes (HSF4, HEYL, SIX2, and ZNF26) and two low-risk genes (ETS2 and SALL1), and validated the OS in two GEO databases (p = 0.0023 for the GSE17536, p = 0.0193 for the GSE29623). To analyze the genetic and epigenetic changes of these six risk-related TFs, a unified bioinformatics analysis was conducted. Among them, ZNF26 is progressive in CRC and its high expression is linked with a poor diagnosis as well. Knockdown of ZNF26 inhibits the proliferative capacity of CRC cells. Moreover, the positive association between ZNF26 and cyclins (CDK2, CCNE2, CDK6, CHEK1) was also identified. Therefore, as a novel biomarker, ZNF26 may be a promising candidate in the diagnosis and prognostic evaluation of colorectal cancer.

6.
Oncogene ; 40(19): 3364-3377, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33863999

RESUMO

Colorectal cancer (CRC) is one of the leading cancers worldwide, accounting for high morbidity and mortality. The mechanisms governing tumor growth and metastasis in CRC require detailed investigation. The results of the present study indicated that the transcription factor (TF) myocyte enhancer factor 2A (MEF2A) plays a dual role in promoting proliferation and metastasis of CRC by inducing the epithelial-mesenchymal transition (EMT) and activation of WNT/ß-catenin signaling. Aberrant expression of MEF2A in CRC clinical specimens was significantly associated with poor prognosis and metastasis. Functionally, MEF2A directly binds to the promoter region to initiate the transcription of ZEB2 and CTNNB1. Simultaneous activation of the expression of EMT-related TFs and Wnt/ß-catenin signaling by MEF2A overexpression induced the EMT and increased the frequency of tumor formation and metastasis. The present study identified a new critical oncogene involved in the growth and metastasis of CRC, providing a potential novel therapeutic target for CRC intervention.


Assuntos
Neoplasias Colorretais/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/biossíntese , beta Catenina/biossíntese , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Transição Epitelial-Mesenquimal , Xenoenxertos , Humanos , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Gradação de Tumores , Taxa de Sobrevida , Ativação Transcricional , Regulação para Cima , Via de Sinalização Wnt , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
7.
Cell Death Dis ; 11(7): 604, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732864

RESUMO

Engrailed-2 (EN2), a member of the engrailed homeobox family, has been shown to be abnormally expressed in a variety of cancers. However, the expression and the clinical significance of EN2 in colorectal cancer (CRC) are largely unknown. Firstly, we found that EN2 acted as an oncogene in CRC. EN2 was upregulated in colorectal cancer tissues compared with adjacent normal tissues. Higher EN2 expression was significantly associated with poorer survival rate. Knockdown of EN2 markedly inhibited proliferation and migration capacities of SW480 cells in vitro, and suppressed tumorigenicity in vivo. Mechanistically, Chemokine ligand 20 (CCL20), a member of the C-C motif chemokine subfamily, was identified as a direct target gene of EN2 in CRC. CCL20 expression was positively correlated with EN2 expression in CRC tissues. Moreover, EN2 promoted the proliferation and migration of CRC cells by regulating the expression of CCL20 in vitro. These results suggest that EN2 plays a critical role in the CRC tumor progression and may serve as a potential target for CRC prevention and therapy.


Assuntos
Quimiocina CCL20/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Oncogenes , Idoso , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Núcleo Celular/metabolismo , Proliferação de Células/genética , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , Regulação para Cima/genética
8.
Oncogene ; 39(20): 3965-3979, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32205869

RESUMO

Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.


Assuntos
Carcinogênese/metabolismo , Transição Epitelial-Mesenquimal , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/biossíntese , Neoplasias Ovarianas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Elementos de Resposta , Proteína 1 Relacionada a Twist/biossíntese , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Complexo Repressor Polycomb 1/genética , Transcrição Gênica , Proteína 1 Relacionada a Twist/genética
9.
Cell Cycle ; 18(14): 1601-1618, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31135262

RESUMO

Ovarian cancer is one type of gynecological malignancies with extremely high lethal rate. Abnormal proliferation and metastasis are regarded to play important roles in patients' death, whereas we know little about the underlying molecular mechanisms. Under this circumstance, our current study aims to investigate the role of hub genes in ovarian cancer. Bioinformatics analysis of the data from GEO and analyses of ovarian cancer samples were performed. Then, the results showed that KIF23, a hub gene, was mainly related to cell cycle and positively associated with poor prognosis. Meanwhile, both miR-424-5p and miR-503-5p directly targeted to 3'UTR of KIF23 to suppress the expression of KIF23 and inhibit ovarian cancer cell proliferation and migration. Furthermore, we discovered that miR-424/503 was epigenetically repressed by hypermethylation in the promoter regions, which directly modulated the expression of KIF23 to improve the oncogenic performance of cancer cells in vitro. Together, our research certifies that miR-424/503 cluster is silenced by DNA hypermethylation, which promotes the expression of KIF23, thereby regulating the proliferation and migration of ovarian cancer cells. Interposing this process might be a novel approach in cancer therapy.


Assuntos
Carcinoma Epitelial do Ovário/genética , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Ovarianas/genética , Regiões 3' não Traduzidas , Carcinogênese/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Metilação de DNA , Bases de Dados de Ácidos Nucleicos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/química , MicroRNAs/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Regiões Promotoras Genéticas , Mapas de Interação de Proteínas
10.
PLoS One ; 14(4): e0214822, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939162

RESUMO

Cervical cancer is the second most deadly gynecological tumor worldwide. MicroRNAs (miRNAs) play very important roles in tumor oncogenesis and progression. The mechanism of post-transcription regulation of WTX gene is still unknown. A series of differential miRNAs were discovered by microarray analysis comparing three pairs of primary cervical cancer specimens and their relapsed tumors from three patients. Quantitative reverse transcriptase PCR (qRT-PCR), Western Blot (WB) and Immunohistochemistry (IHC) was used to detect the expression of miR-4524b-5p and WTX in cervical cell lines and tissues. The biological function of miR-4524b-5p and WTX was investigated through knockdown and overexpression with inhibitor/siRNA and mimic/plasmid in vitro and in vivo. In this study, we found that miR-4524b-5p is highly expressed in relapsed cervical cancer specimens. Combined in vitro and in vivo experiments, showed that miR-4524b-5p could regulate the migration and invasion ability of cervical cancer. Furthermore, we also found that miR-4524b-5p could regulate the migration and invasion of cervical cancer by targeting WTX and that WTX could regulate the expression of ß-catenin. Taken together, our data identified a miR-4524b-5p/WTX/ß-catenin regulatory axis for cervical cancer, and miR-4524b-5p may be a potential target for cervical cancer therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , MicroRNAs/genética , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Transplante de Neoplasias , Proteínas Supressoras de Tumor/antagonistas & inibidores , Neoplasias do Colo do Útero/metabolismo
11.
12.
Cancer Manag Res ; 10: 5113-5124, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464611

RESUMO

OBJECTIVE: Colorectal cancer (CRC) is considered to be the most prevalent malignant tumors that contribute to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We seek to discover a novel biomarker in CRC. MATERIALS AND METHODS: All clinical CRC samples (n=33) were from Xiangya Hospital. We first selected CCNA2 by integrated bioinformatics analysis of four GSE databases. Next, the expression of CCNA2 in tissues and cell lines was verified by quantitative real-time PCR. The effects of CCNA2 on cell growth, proliferation, cell cycle, and apoptosis were examined by in vitro assays. RESULTS: We identified 498 shared DEGs (294 upregulated and 204 downregulated), and the top ten hub genes were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of CCNA2 in CRC tissues is higher than that in normal tissues. The CCNA2 knockdown could significantly suppress CRC cell growth by impairing cell cycle progression and inducing cell apoptosis. CONCLUSION: CCNA2, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis. It could be used as a new biomarker for diagnosis and therapy in CRC.

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