PCAF通过乙酰化GLI1蛋白抑制Hedgehog通路进而发挥其抗肝细胞癌作用的机制研究

Hepatocellular carcinoma (HCC) is the leading malignant tumor in China. In our preliminary investigation, we found PCAF was downregulated in HCC tissues and associated with better prognosis significantly. In addition, via in vitro experiments, we also verified that PCAF inhibited both growth and migration of HCC cells. However, the underlying mechanism of its antitumor function remains unknown. On the other hand, we have confirmed that aberrant activation of Hedgehog/GLI1 (Hh) signaling promoted HCC growth and metastasis, however, the mechanism that Hh signaling was activated aberrantly in HCC is still unclear, either. Recent research revealed that deacetylating GLI1 protein in cytoplasm could activate Hh signaling. In the present project, we try to figure out whether PCAF exerts its anti-HCC effect via activating Hh signaling aberrantly by acetylating GLI1 protein in cytoplasm on the basis of our previous data. Furthermore, we attempt to verify the anti-HCC action of PCAF and the molecular mechanism mentioned above on both nude mouse model and PCAF knockout mouse model. The aim of this project is to investigate the molecular mechanism of both the anti-HCC effect of PCAF and Hh signaling activating aberrantly in HCC in order to provide the scientific basis to exploit novel targeting agents and predictive biomarkers for HCC clinically.

肝细胞癌（HCC）是我国最为常见的恶性肿瘤之一。我们前期研究发现PCAF在HCC组织中表达明显减少，其表达与HCC较好的预后明显正相关。后进一步通过体外实验证实PCAF具有抑制HCC生长和迁移的作用，但其分子机制不明。另一方面，我们已经证实HCC中异常激活的Hedgehog/GLI1（Hh）通路促进肿瘤生长和转移，但是其异常激活机制不清。近期有实验证实抑制细胞浆中GLI1蛋白乙酰化可以异常激活Hh通路。本项目是既往工作的深入，拟通过免疫共沉淀等体外实验证实PCAF乙酰化细胞浆中GLI1蛋白进而抑制HCC细胞Hh通路发挥抑癌作用，进而在裸鼠HCC模型和PCAF敲除鼠HCC模型上验证PCAF的抑癌作用以及上述分子机制。本项目旨在阐明PCAF抗HCC作用的分子机制以及HCC中Hh通路异常激活机制，并在动物模型上证实PCAF的抗HCC作用，为临床开发新的HCC靶向治疗药物和预后标志物奠定理论基础。

肝细胞癌（HCC）是我国最为常见的恶性肿瘤之一。我们前期研究发现PCAF在HCC组织中表达明显减少，其表达与HCC较好的预后明显正相关。后进一步通过体外实验证实PCAF具有抑制HCC生长和迁移的作用，但其分子机制不明。另一方面，我们已经证实HCC 中异常激活的Hedgehog/GLI1（Hh）通路促进肿瘤生长和转移，但是其异常激活机制不清。近期有实验证实抑制细胞浆中GLI1蛋白乙酰化可以异常激活Hh通路。本项目是既往工作的深入，拟通过免疫共沉淀等体外实验证实PCAF乙酰化细胞浆中GLI1蛋白进而抑制HCC细胞Hh通路发挥抑癌作用，进而在裸鼠HCC模型和PCAF敲除鼠HCC模型上验证PCAF的抑癌作用以及上述分子机制。本项目旨在阐明PCAF抗HCC作用的分子机制以及HCC中Hh通路异常激活机制，并在动物模型上证实PCAF的抗HCC作用，为临床开发新的HCC靶向治疗药物和预后标志物奠定理论基础。