The epigenetic mechanism of long non-coding RNA in cancer

描述（由申请人提供）：癌症是一种涉及基因组多步变化的遗传疾病。人类基因组包含约25,000个蛋白质编码基因，占总基因组的不到2%，而高达70%的人类基因组被转录成RNA，产生成千上万的非编码RNA。最近发现的非编码rna，包括小的非编码rna如microRNA，极大地改变了我们对癌症的认识。然而，对长非编码转录本的研究还处于起步阶段。长链非编码RNA （lncRNAs）在操作上被定义为大于200nt的RNA转录物，似乎不具有蛋白质编码潜力。越来越多的证据表明lncRNA参与了癌症的发生和发展。一种新的致癌lncRNA， FAL1 (Focal amplification lncRNA 1)，最近被PI的实验室发现。我们的初步数据表明：FAL1的扩增和高表达与癌症预后较差相关；FAL1 RNA与表观遗传抑制因子BMI1结合，调节其稳定性；敲低FAL1会增加许多基因的转录，包括CDKN1A；FAL1的致癌性部分归因于其抑制p21的表达；和fal1特异性小干扰rna在体内显著抑制肿瘤生长。因此，我们假设新的致癌lncRNA FAL1通过其与BMI1的相互作用在表观遗传学上调控多种癌症相关通路，并且对FAL1功能的研究可能为癌症患者提供新的生物标志物和治疗靶点。我们将通过以下具体目标来检验这一假设：描述FAL1调节BMI1稳定性的分子机制。具体目标2。鉴定癌细胞中受FAL1/BMI1表观遗传调控的分子网络。具体目标3。研究FAL1在癌症发生和发展中的细胞功能。

DESCRIPTION (provided by applicant): Cancer is a genetic disease involving multi-step changes in the genome. The human genome contains ~25,000 protein-coding genes, representing less than 2% of the total genome, whereas up to 70% of the human genome is transcribed into RNA, yielding many thousands of non-coding RNAs. The recent discovery of non-coding RNAs, including small non-coding RNAs such as microRNA, has dramatically altered our understanding of cancer. However, research on long non-coding transcripts is still in its infancy. Long non-coding RNAs (lncRNAs) are operationally defined as RNA transcripts larger than 200 nt that do not appear to have protein-coding potential. Rapidly accumulating evidence indicates that lncRNA is involved in the initiation and progression of cancer. A novel oncogenic lncRNA, FAL1 (Focal Amplified lncRNA 1), has recently been identified by the PI's laboratory. Our preliminary data indicate that: amplification and high expression of FAL1 are correlated with poorer outcomes in cancer; FAL1 RNA associates with the epigenetic repressor BMI1, regulating its stability; knockdown of FAL1 increases the transcription of a number of genes, including CDKN1A; the oncogenicity of FAL1 is partially attributable to its repression of p21 expression; and FAL1-specific small interfering RNAs significantly inhibit tumor growth in vivo. Therefore, we hypothesize that the novel oncogenic lncRNA FAL1 epigenetically regulates multiple cancer-associated pathways via its interaction with BMI1, and that the investigation of the function of FAL1 may provide novel biomarkers and therapeutic targets for patients with cancer. We will test this hypothesis through the following specific aims: Specific Aim 1. Characterize the molecular mechanisms by which FAL1 regulates BMI1 stability. Specific Aim 2. Identify the molecular network epigenetically regulated by FAL1/BMI1 in cancer cells. Specific Aim 3. Examine the cellular functions of FAL1 in cancer initiation and progression.