RESUMO
Cancer is a life-threatening disease, but cancer therapies based on epigenetic mechanisms have made great progress. Enhancer of zeste homolog 2 (EZH2) is the key catalytic component of Polycomb repressive complex 2 (PRC2) that mediates the tri-methylation of lysine 27 on histone 3 (H3K27me3), a well-recognized marker of transcriptional repression. Mounting evidence indicates that EZH2 is elevated in various cancers and associates with poor prognosis. In addition, many studies revealed that EZH2 is also involved in transcriptional repression dependent or independent of PRC2. Meanwhile, long non-coding RNAs (lncRNAs) have been reported to regulate numerous and diverse signaling pathways in oncogenesis. In this review, we firstly discuss functional interactions between EZH2 and lncRNAs that determine PRC2-dependent and -independent roles of EZH2. Secondly, we summarize the lncRNAs regulating EZH2 expression at transcription, post-transcription and post-translation levels. Thirdly, we review several oncogenic pathways cooperatively regulated by lncRNAs and EZH2, including the Wnt/ß-catenin and p53 pathways. In conclusion, lncRNAs play a key role in the EZH2-regulated oncogenic network with many fertile directions to be explored.
Assuntos
Carcinogênese , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo , Animais , HumanosRESUMO
Triple negative breast cancer (TNBC) has poor prognosis due to lack of biomarker and therapeutic target. Emerging research has revealed long noncoding RNAs (lncRNAs) are involved in breast cancer progression, but their functions and regulatory mechanisms remain poorly understood, especially in TNBC. In this study, we performed lncRNA microarray analysis of five TNBC samples and their matched normal tissues, and discovered a number of differentially expressed lncRNAs. We identified an antisense lncRNA, HYOU1-AS, which is transcribed from the opposite strand of the hypoxia up-regulated 1 (HYOU1) gene, enriched in the nucleus and highly expressed in TNBC. HYOU1-AS knockdown could inhibit the proliferation and migration of the TNBC MDA-MB-231 cells, and reduce their xenograft tumor formation in nude mice. In mechanistic studies, we found that HYOU1-AS could promote the expression of HYOU1, a proliferative gene, through competitively binding to hnRNPA1, an RNA-binding protein, to relieve its post-transcriptional inhibition of the HYOU1 mRNA. Consistently, increased HYOU1 levels correlated with poor clinical outcomes of breast cancer patients based on our study of the TCGA database. Overall, our data indicated that the lncRNA HYOU1-AS promoted TNBC progression through upregulating HYOU1.
Assuntos
Perfilação da Expressão Gênica/métodos , Proteínas de Choque Térmico HSP70/genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Animais , Ligação Competitiva , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Sobrevida , Ativação Transcricional , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
As a member of the homeobox gene family, HOXC10 plays an important role in cell differentiation and embryonic development of mammals. Increasing evidence also suggests a regulatory role of HOXC10 in oncogenesis, but the regulation of HOXC10 gene expression is relatively understudied. In this report, we revealed that the HOXC10 promoter contains multiple G-tracts in its negative strand and has high potential of forming G-quadruplex structures. In circular dichroism studies, synthesized oligonucleotides based on the G-rich region of 241-297 base pairs upstream of the HOXC10 transcription start site showed molar ellipticity at specific wavelengths characteristic of G-quadruplex structures. Analyses of these oligonucleotides by native polyacrylamide gel electrophoresis, gel-shift assay, immunostaining and replication stop assay revealed formation of multiple types of G-quadruplex structures in presence of potassium and lithium ions. In reporter assays, mutations or deletion of the G-tracts could differentially impact the expression of Gaussia luciferase downstream of the HOXC10 promoter. Additionally, CHD7, a chromatin remodeling protein with DNA helicase activity, could associate with the HOXC10 promoter and likely unwind the G-quadruplex structures to enhance its gene expression.
Assuntos
Neoplasias da Mama/genética , DNA Helicases/fisiologia , Proteínas de Ligação a DNA/fisiologia , Quadruplex G , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/fisiologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Dicroísmo Circular , Feminino , Humanos , Regiões Promotoras GenéticasRESUMO
Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications. Recent studies reveal a proliferative role of YY1 in oncogenesis. Consistently, YY1 overexpression has been observed in various human malignancies and its levels correlate with poor prognoses of many types of cancers. In this review, we focus on the signaling pathways and regulatory proteins that YY1 modulates to promote tumor cell growth, proliferation, migration and metastasis. We also discuss the signals and molecules that regulate YY1 expression and function in cancer-related context. Based on the expression feature and regulatory activities in tumor cells, YY1 possesses a great potential as a biomarker for many cancers and can serve as a therapeutic target clinically to impede cancer development and progression or sensitize cancer cells to anticancer drugs.
