BRD4是重要的肿瘤驱动基因，主要通过转录共激活作用促进myc等原癌基因的表达。BRD4的活性调控机制尚未见报道。项目初步研究发现lncRNA NR_147908与BRD4结合且抑制BRD4靶基因的转录；在肺癌组织中NR_147908表达显著下调，高表达/敲低NR_147908影响肺癌细胞的凋亡、增殖。我们提出科学假说：NR_147908与BRD4结合，阻断BRD4与组蛋白等结合从而抑制BRD4的转录共激活作用。NR_147908表达下调，致使BRD4异常激活，从而导致肿瘤的恶性进展及耐药。接下来将通过RNA pull-down、siRNA-芯片进一步确定NR_147908与BRD4的相互作用以及调控机制；在细胞与动物水平验证NR_147908通过BRD4调控肿瘤的进展；在肺癌、骨肉瘤标本中分析NR_147908的临床意义。本课题有望揭示NR_147908调控BRD4的机制及临床意义。

BRD4 functions as a key pro-oncogene through transcriptionally co-activating multiple pro-oncogene including c-Myc, Bcl2 ect. However, the factors that regulate the transcriptionally co-activating function of BRD4 is unknown. We had identified that lncRNA NR_147908 interacted with BRD4 and inhibited the transcription of BRD4 down-stream genes. Besides, NR_147908 level was down-regulated in lung cancer and JQ1 resistant lung cancer cells compared with their pars-carcinoma tissues and parent cells. We hypothesize that NR_147908 interacts with BRD4 and blocks the co-transcriptional activity of BRD4. The down-regulation of NR_147908 in cancer cells results in the up-regulated activity of BRD4, which leads to the tumorigenesis, progression of cancer cells and resistance of cancer cells to BRD4 inhibitors. In the following study, we will examine the mechanisms by which NR_147908 regulates the stability of BRD4 using RNA pull-down, microarray, etc. We will also test the role of NR_147908 on the progression of lung cancer and osteosarcoma in vitro and in vivo. In addition, we will evaluate the clinical significance of NR_147908 and the correlation between NR_147908 and BRD4 downstream genes. Our study might be prove to be clinically significant in the future.