Unknown,Transcriptomics,Genomics,Proteomics

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Coordinated regulation of polycomb group complexes through microRNAs in cancer

ABSTRACT: To determine the altered mRNA expression signatures upon overexpressing EZH2 regulated microRNAs in cancer. To identify EZH2 regulated microRNAs in cancer. Two-condition experiment: Each EZH2 microRNA was overexpressed and compared to a control RNA in BT549 breast cancer cells. In DU145 prostate cancer cell EZH2 was knocked down and comapred to EZH2 scrambled siRNA. Other cell lines were monitored for miRNA expression as they are known to have high endogenous levels of EZH2.

ORGANISM(S): Homo sapiens

SUBMITTER: Christopher Maher

PROVIDER: E-GEOD-26996 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Coordinated regulation of polycomb group complexes through microRNAs in cancer.

Cao Qi Q Mani Ram-Shankar RS Ateeq Bushra B Dhanasekaran Saravana M SM Asangani Irfan A IA Prensner John R JR Kim Jung H JH Brenner J Chad JC Jing Xiaojun X Cao Xuhong X Wang Rui R Li Yong Y Dahiya Arun A Wang Lei L Pandhi Mithil M Lonigro Robert J RJ Wu Yi-Mi YM Tomlins Scott A SA Palanisamy Nallasivam N Qin Zhaohui Z Yu Jindan J Maher Christopher A CA Varambally Sooryanarayana S Chinnaiyan Arul M AM

Cancer cell 20110801 2

Polycomb Repressive Complexes (PRC1 and PRC2)-mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are upregulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs, in turn, regulate the expression of PRC1 proteins BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated m ...[more]

PMID: 21840484

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Project description:Renal cancer accounts for 2% to 3% of all adult malignancies in the US. In 2011 more than 64,770 new cases and 13,000 deaths were reported and the incidence is steadily increasing by 2.5% per year. Clear cell renal carcinoma (ccRCC) represents the majority (85% to 90%) of adult kidney cancers and is the most malignant. This cancer is characterized by an early loss of the von Hippel-Lindau tumor suppressor (VHL) on short arm of chromosome 3 in the majority of tumors (80%). It is a classic knowledge that loss of VHL results in an increased accumulation and activity of the hypoxia-inducible transcription factor (HIF), which in turns activates expression of genes promoting tumor growth. In that respect, induction of angiogenic factors induces blood flow through the tumors and delivery of nutrients and oxygen to cancer cells, while induction of genes inducing anaerobic glycolysis supports adaptation to reduced nutrients availability and shifts towards metabolic pathways promoting tumor growth. Recently we have discovered another tumor suppressing pathway regulated by VHL. We found that VHL is a major regulator of the process of macroautophagy (autophagy) (ref). We identified that VHL induces expression of a microRNA, miR-204, which in turn inhibits activity of a major regulator required for the formation of autophagosome, LC3B. LC3B-mediated autophagy is necessary for the ccRCC tumor growth, and inhibition of this process by VHL and miR-204 significantly contributes to the tumor suppression. Most importantly, we discovered that VHL by inhibiting activity of HIF, induced expression and activity of an LC3B paralog, LC3C. In contrast to LC3B, LC3C acts as a tumor suppressor, indicating the specificity and complexity of different autophagic programs. Integrating these novel data with the established role of VHL in regulating angiogenesis produces a more global picture of VHL as a master tumor suppressor that regulates nutrient access for renal cancer cells from both extracellular and intracellular sources. In the process of searching for other genes induced by VHL that could participate in the tumor suppressing activity of VHL, we discovered that reconstitution of VHL in RCC cells induces enrichment of genes expressed from the Smith-Magenis locus (SM), located on the short arm of chromosome 17p11.2. Smith-Magenis syndrome is a complex neurobehevioural disorder, characterized by intellectual impairment, craniofacial and skeletal anomalies and sleep disturbance. Recently, deletions or mutations of one specific gene in the SM locus, RAI1, (retinoic acid induced 1), were shown to be responsible for the syndrome. Interestingly, this locus contains another kidney tumor suppressor gene, folliculin (FLCN), of which activity is lost in the genetic dominant disorder, Birt-Hogg-Dube syndrome (BHD). BHD is characterized by skin fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, as well as renal cancer of mixed histological types, including chromophobe, oncocytic, clear cell and papillary type. Here we show that VHL regulates expression of FLCN, and in turn FLCN contributes to the VHL-mediated suppression of tumor growth. Two-condition experiment, VHL(-) vs. VHL(+). 4 biological replicates in each group. Two dual-channel arrays with VHL(+) on Cy5 and VHL(-) on Cy3, and two dual-channel arrays with flipped samples.

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Coordinated regulation of polycomb group complexes through microRNAs in cancer

Publications

Coordinated regulation of polycomb group complexes through microRNAs in cancer.

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