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性疾病。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为RNA，产生数千个非编码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理解。然而，对长非编码转录本的研究仍处于起步阶段。长链非编码RNA（lncRNA）是指长度大于200 nt的RNA转录本，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。PI实验室最近鉴定出一种新的致癌lncRNA，即Focal Amplified lncRNA 1。我们的初步数据表明：扩增和高表达的p21与癌症的预后较差相关; p21 RNA与表观遗传阻遏物BMI 1相关，调节其稳定性; p21的敲低增加了许多基因的转录，包括CDKN 1A; p21的致癌性部分归因于其对p21表达的抑制;并且，在活体中，EST 1特异性小干扰RNA显著抑制肿瘤生长。因此，我们假设，新的致癌lncRNA p31通过与BMI 1的相互作用表观遗传地调节多种癌症相关的途径，并且对p31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：具体目标1。描述BMI 1调节BMI 1稳定性的分子机制。具体目标2。确定癌细胞中由BMI 1/BMI 1表观遗传调控的分子网络。具体目标3。检查在癌症的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.