核小体结合蛋白（NSBP1）通过染色质重塑调控前列腺癌发生发展的分子机制研究

Nucleosomal binding protein 1 (NSBP1), also known as HMGN5, is a member of high-mobility group nucleosome binding domain (HMGN) family and plays an important role in chromatin remodeling. NSBP1 promotes chromatin decondensation and conversion from heterochromatin to euchromatin by competing with histone H1 in nucleosome binding. As its loosen structure, euchromatin is prone to interacting with trans-acting factor and promotes DNA replication and transcription. NSBP1 is overexpressed in prostate cancer tissue, which was first identified by our group, and our latter investigation proved that NSBP1 is involved in promoting prostate cancer cells proliferation, anti-apoptosis and invasion. The latest studies shows that the expression of NSBP1 relates to radiotherapy insensitivity of prostate cancer cells, suggesting the high clinical application value of NSBP1. Nevertheless, the mechanism through which NSBP1 promotes prostate cancer initiation and development and whether it is related to chromatin remodeling are still unknown. It heavily hinders the research on applying NSBP1 into prostate cancer treatments. This project aims at determining the relationship between tumor promotion and chromatin remodeling functions of NSBP1 through molecular and cellular biologic technology. The accomplishment of this project will provide a theoretical basis for personalized therapy on prostate cancer.

核小体结合蛋白（NSBP1）又名HMGN5，属于高迁移族核小体结合蛋白家族成员，对染色质重塑调节发挥重要的作用。NSBP1通过与组蛋白H1竞争结合核小体抑制H1与染色质的结合，调节染色质重塑，促进异染色质向常染色质转变。常染色质因其易于基因转录表达、DNA复制和DNA损伤及修复，与肿瘤发生发展密切相关。本课题组首次发现NSBP1在前列腺癌组织中高表达，并在后续系列研究中证实NSBP1具有很强的促进前列腺癌细胞增殖浸润和抑制凋亡的作用，且与癌细胞对放化疗敏感性相关，具有很高的临床应用价值。然而NSBP1如何发挥其促癌作用以及该作用是否与其染色质重塑功能相关均不清楚，这成为了以NSBP1为靶点的前列腺癌治疗转化研究的瓶颈。本项目拟通过分子生物学手段解析NSBP1促进前列腺癌发生发展的作用与其染色质重塑功能的关系，为以NSBP1为靶点的前列腺癌精准治疗提供理论依据。

前列腺癌是男性最常见的恶性肿瘤，目前放射治疗已经成为原发前列腺癌根治治疗和去势抵抗前列腺癌辅助治疗的重要手段，然而部分患者在放射治疗后存在放疗抵抗，较早出现生化复发，影响治疗效果。本课题组前期研究发现高迁移率核小体结合蛋白5（High mobility nucleosome binding domain 5，HMGN5），又称核小体结合蛋白1（Nucleosome binding protein 1，NSBP1）在前列腺癌组织中表达量明显高于正常前列腺组织和良性增生的前列腺组织，且HMGN5在前列腺癌细胞中的表达量与细胞对放射治疗的抵抗相关，在前列腺癌细胞中敲低HMGN5后可以增加前列腺癌细胞放疗敏感性，然而具体作用机制并不清楚。在本项目研究中，我们通过pulldown和免疫共沉淀实验发现HMGN5能够和DNA修复蛋白Ku70相互结合，并调节后者的蛋白质稳定性，过表达HMGN5后Ku70蛋白表达明显增加，并进一步促进了细胞内的DNA损伤修复，维持细胞存活能力，增强前列腺癌细胞对防止治疗的抵抗能力，该研究为前列腺癌患者的精准诊疗提供了理论和实践基础。