癌蛋白HBXIP辅激活核受体LXR调节脂肪酸代谢对乳腺癌生长的作用及其分子机制研究

代谢性核受体LXR为配体依赖激活的转录因子。我们前期研究发现，癌蛋白HBXIP可配体非依赖结合并激活LXR，进而促进乳腺癌细胞中脂肪酸合成信号通路。生物信息学发现HBXIP含有与核受体结合的辅抑制子CoRNR模序。迄今肿瘤细胞通过非配体依赖方式激活LXR的作用及其分子机制尚不清楚。本项目拟从分子、细胞、组织和动物等层面深入探讨HBXIP配体非依赖辅激活LXR/SREBP-1c的作用及其分子机制，确定HBXIP、LXR和SREBP-1c启动子之间结合的结合域，阐明HBXIP的CoRNR及其两侧序列、HBXIP募集CBP/p300与配体非依赖激活LXR/SREBP-1c通路的关系，探明HBXIP对LXR/SREBP-1c下游靶基因FASN的作用及其与乳腺癌脂肪酸代谢和生长的关系。本研究将提供癌蛋白作为核受体辅激活因子激发脂肪酸代谢促进肿瘤生长的新机制。

The nuclear receptor LXR is a ligand-dependent activated transcription factor. Our previous study showed that the oncoprotein hepatitis B X-interacting protein (HBXIP) was able to interact with LXR in a ligand-independent manner, leading to activation of fatty acid synthesis singnaling in breast cancer cells.Interestingly,bioinformatics showed that HBXIP contained a cosuppressor CoRNR motif, which physically interacts with nuclear receptor.However,the mechaniasm of LXR activation in a ligand-independent manner in cancer cells remains unclear. In this project, we will further explore the role and mechanism of HBXIP in coactivation of LXR/SREBP-1c in a ligand-independent manner at the levels of molecule, cell, tissue and animal. The main contents are as follows: identify the binding domains among HBXIP,LXR and SREBP-1c promoter; determine the relationship between HBXIP and unliganded activation of LXR/SREBP-1c pathway involved in CoRNR motif and its flank sequences of HBXIP,and recruitment of CBP/p300 by HBXIP; clearly investigate the effect of HBXIP on the downstream target gene FASN of LXR/SREBP-1c, and its relationship with lipid metabolism and tumor growth in breast cancer. This study will provide a novel mechanism by which oncoproteins as nuclear receptor coactivators are able to stimulate fatty acid metabolism to promote tumor growth.