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1.
J Cancer ; 13(5): 1530-1539, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35371306

RESUMO

DEAD-box RNA helicase 21 (DDX21), is a nucleolar protein harboring ATP-dependent double-stranded RNA unwinding activities, essential in rRNA processing and ribosome biogenesis. However, its role in colorectal cancer (CRC) progression remains unclear. In this study, we show that knockdown of DDX21 significantly inhibited CRC cell proliferation and blocked cell cycle at the G2/M phase. Gene profile analysis and ChIP assays revealed that DDX21 activated CDK1 gene expression through binding to the gene promoter. In addition, we found that DDX21 directly recruited WDR5 to enhance trimethylation of histone H3 on Lys 4 (H3K4me3) on the CDK1 promoter. Importantly, elevated expression of DDX21 in CRC patients was positively correlated with expression of CDK1, and these CRC patients had shorter overall survival. These findings reveal a critical novel role of DDX21 in transcriptional and epigenetic control of CRC cell proliferation. Taken together, this study uncovers that DDX21 interacted with WDR5 to promote colorectal cancer cell proliferation by activating CDK1 expression, suggesting that targeting DDX21 may be an alternative new strategy for CRC treatment.

2.
Theranostics ; 10(10): 4437-4452, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292506

RESUMO

The proto-oncogene c-Myc regulates multiple biological processes mainly through selectively activating gene expression. However, the mechanisms underlying c-Myc-mediated gene repression in the context of cancer remain less clear. This study aimed to clarify the role of PRMT5 in the transcriptional repression of c-Myc target genes in gastric cancer. Methods: Immunohistochemistry was used to evaluate the expression of PRMT5, c-Myc and target genes in gastric cancer patients. PRMT5 and c-Myc interaction was assessed by immunofluorescence, co-immunoprecipitation and GST pull-down assays. Bioinformatics analysis, immunoblotting, real-time PCR, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Results: We found that c-Myc directly interacts with protein arginine methyltransferase 5 (PRMT5) to transcriptionally repress the expression of a cohort of genes, including PTEN, CDKN2C (p18INK4C), CDKN1A (p21CIP1/WAF1), CDKN1C (p57KIP2) and p63, to promote gastric cancer cell growth. Specifically, we found that PRMT5 was required to promote gastric cancer cell growth in vitro and in vivo, and for transcriptional repression of this cohort of genes, which was dependent on its methyltransferase activity. Consistently, the promoters of this gene cohort were enriched for both PRMT5-mediated symmetric di-methylation of histone H4 on Arg 3 (H4R3me2s) and c-Myc, and c-Myc depletion also upregulated their expression. H4R3me2s also colocalized with the c-Myc-binding E-box motif (CANNTG) on these genes. We show that PRMT5 directly binds to c-Myc, and this binding is required for transcriptional repression of the target genes. Both c-Myc and PRMT5 expression levels were upregulated in primary human gastric cancer tissues, and their expression levels inversely correlated with clinical outcomes. Conclusions: Taken together, our study reveals a novel mechanism by which PRMT5-dependent transcriptional repression of c-Myc target genes is required for gastric cancer progression, and provides a potential new strategy for therapeutic targeting of gastric cancer.


Assuntos
Adenocarcinoma/metabolismo , Histonas/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Progressão da Doença , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metilação , Regiões Promotoras Genéticas , Proto-Oncogene Mas , Neoplasias Gástricas/patologia
3.
Aging (Albany NY) ; 12(2): 1304-1321, 2020 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-31982864

RESUMO

Aurora kinase B (AURKB) triggers the phosphorylation of serine 10 on histone H3 (H3S10ph), which is important for chromosome condensation and cytokinesis during mitosis in mammals. However, how exactly AURKB controls cell cycle and contributes to tumorigenesis as an oncoprotein under pathological conditions remains largely unknown. Here, we report that AURKB promotes gastric cancer cell proliferation in vitro and in vivo. Silencing AURKB expression inhibits gastric cell proliferation and arrests the cell cycle in G2/M phase. We demonstrate that cyclin D1 (CCND1) is a direct downstream target of AURKB that plays a key role in gastric cancer cell proliferation. AURKB is able to activate the expression of CCND1 through mediating H3S10ph in the promoter of the CCND1 gene. Furthermore, we show that AZD1152, a specific inhibitor of AURKB, can suppress the expression of CCND1 in the gastric cancer cells and inhibit cell proliferation in vitro and in vivo. Importantly, we found that high AURKB and CCND1 expression levels are correlated with shorter overall survival of gastric cancer patients. This study demonstrates that AURKB promotes gastric tumorigenesis potentially through epigenetically activating CCND1 expression, suggesting AURKB as a promising therapeutic target in gastric cancer.


Assuntos
Aurora Quinase B/metabolismo , Ciclina D1/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Aurora Quinase B/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Ativação Enzimática , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Fosforilação , Prognóstico , Ligação Proteica , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
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