基因通读产生的 circRNA H6S5（HIF1α-SNAPC1）与嵌合蛋白 pH6S5: 生物学功能及其在前列腺癌中的作用

We found several protein-encoding chimeric circular RNAs derived from transcriptional read-through of HIF1α and SNAPC1 genes on chomosome 14. We explored the structure and function of circRNA H6S5, one of these read-through transcripts derived by this novel mechanism, which consisted of exons 6-8 of the transcription factor HIF1α and exons 2-4 of the transcription co-activator SNAPC1. The chimeric protein pH6S5 encoded by this read-through circRNA consisted of the HIF1α PAS B domain and the SNAPc domain of SNAPC1. This project intends to investigate the functions of the chimeric circRNA H6S5 and the pH6S5 protein. Potential functions of circRNA H6S5 include transciptional activation of HIF1α and SNAPC1 by recruiting transactivators, and suppression of inhibitory microRNAs targeting HIF1α and SNAPC1 mRNA. The chimeric protein pH6S5 may promote HIF1α/ARNT heterodimerization, and facilitate SNAPC complex formation, resulting in enhanced expression of down-stream target genes regulated by HIF1α/ARNT. We will also analyze the roles of the overexpressed circRNA H6S5 and pH6S5 in prostate adenocarcinoma...Key words: gene read-through; chimeric circular RNA; chimeric protein; HIF1α; prostate adenocarcinoma

我们发现由14号染色体上HIF1α和SNAPC1两相邻基因转录通读形成的数种嵌合circRNA及其编码的嵌合蛋白。这一新机制产生的嵌合circRNA H6S5含有转录因子HIF1α的6-8号外显子和转录共激活因子SNAPC1的2-5号外显子序列，编码嵌合蛋白质pH6S5（含HIF1α PAS B和SNAPC1 SNAPc结构域）。本课题拟深入研究嵌合circRNA H6S5和嵌合蛋白pH6S5的功能。circRNA H6S5可能结合/募集转录激活蛋白，或作为ceRNA解除microRNA对HIF1α和SNAPC1基因的抑制，促进HIF1α和SNAPC1表达。预测嵌合蛋白pH6S5具有促进HIF1α/ARNT二聚体形成和促进SNAPC复合物形成的双重作用，增强HIF1α/ARNT调控的下游靶基因表达。课题亦将分析嵌合circRNA H6S5和嵌合蛋白pH6S5高表达在前列腺癌中的作用。

本研究发现由14号染色体上HIF1α和SNAPC1两相邻基因转录通读形成的数种嵌合circRNA及其编码的嵌合蛋白。课题主要研究这一新机制产生的嵌合circRNA H6S5，该嵌合RNA在前列腺癌中表达增加；含有转录因子HIF1α的6-8号外显子和转录共激活因子SNAPC1的2-5号外显子序列，具开放阅读框，可编码嵌合蛋白质pH6S5（含HIF1α PAS B和SNAPC1 SNAPc结构域）。课题探索了嵌合circRNA H6S5和嵌合蛋白pH6S5的功能；实验显示circRNA H6S5可作为分子海绵/内源竞争性RNA（ceRNA）解除miR-4743-3p等microRNAs 对HIF1α和SNAPC1基因的转录后负调控作用，增加HIF1α和SNAPC1基因表达水平；circRNA H6S5 /pH6S5可促进HIF1α/ARNT二聚体形成，结合/募集转录激活蛋白至靶基因（包括ZEB1）启动子区，增强HIF1α/ARNT调控的下游靶基因表达。嵌合circRNA H6S5的表达增加前列腺癌细胞增殖、迁移和侵袭能力。上述研究结果显示前列腺癌中基因转录通读形成的嵌合circRNA作为ceRNA，其编码蛋白质作为癌基因转录调控分子，增强前列腺癌细胞增殖和侵袭能力的新机制，具有潜在临床应用价值。