BAI-1调控染色质活性位点抑制Warburg效应在肺癌转移中的研究

Warburg effect provided the major energy source for tumoregenesis and promoted metastasis. Alteration of chromatin active sites significantly influenced the Warburg effect. Brain angiogenesis inhibitor 1 (BAI1) was a candidate circulating lung cancer marker in our previous works. The functional researches indicated that over-expression of BAI1 in A549 cells dramatically inhibited Warburg effect and suppressed the invasion of A549 cells by promoting the remodeling of cytoskeletons. Further studies indicated that BAI1 induced emergence of chromatin active sites. Based on these observations we provided the hypothesis: BAI1 could suppress the Warburg effect by regulating the active sites of chromatin and finally inhibited the metastasis of lung cancer. To verify this hypothesis, BAI over-expression and knock-out cell models, as well as lung cancer metastasis model established in SCID-IL2γ-/- mice and the following studies will be conducted: ① To investigate the critical molecules and mechanisms in suppressing Warburg effect by regulating the activation of chromatin; ② To validate the mechanisms of cytoskeleton remodeling; ③ To study the variation of organ tropism of lung cancer cells regulated by BAI1. Our study will provide new mechanism in regulation of chromatin active sites on Warburg effect and also provide new targets and research basis on metabolism therapy.

Warburg效应是肿瘤细胞主要能量来源并促进其转移；染色质活性位点变化显著影响Warburg效应。我们发现脑血管生长抑制因子1（BAI1）是肺癌候选血液标志物；A549细胞过表达BAI1后抑制Warburg效应，并通过促细胞骨架重排抑制转移；进一步研究发现BAI1影响多个糖代谢酶表达及活性，ATAC-Seq分析发现BAI1诱导糖代谢相关染色质活性位点的产生。前期结果提示：BAI1可能通过调控染色质活性位点抑制Warburg效应，进而抑制肺癌转移。为此本项目拟构建肺癌细胞BAI1过表达与敲除模型及SCID-IL2γ-/-肺癌转移小鼠模型，深入研究BAI1调控染色质活性位点抑制Warburg效应、通过促进细胞骨架重排抑制转移、以及影响肺癌细胞器官嗜性的关键因子及分子机制。研究结果有望提出染色质活性位点变化影响Warburg效应的新调控机制，进而为从代谢角度抑制肿瘤转移研究奠定基础。

BAI1 是G 蛋白偶联受体家族（G Protein-Coupled Receptors, GPCR）成员，在多种肿瘤组织中低表达，且与患者不良预后相关，但其在肺癌中相关研究需进一步探索。本研究检测了BAI1在肺癌组织的表达水平，体内外证实了其对肺癌发展的抑制作用。进一步发现BAI1通过调节活性位点诱导代谢重编程，包括糖代谢以及氨基酸代谢。在进一步的机制探索中我们发现，对于不同的代谢进程，其中通过不同的代谢靶点进行调控，在糖代谢的重编程中，BAI1通过上调的SCD1表达进而抑制了HMGCR的表达方式影响了代谢重编程，最终引起了细胞生物学行为的变化。在氨基酸代谢的重编程中，BAI1过表达影响了COUP-TF及ARP-1 的甲基化，进而造成COUP-TF及ARP-1 基因表达量下调，从而激活了ALDH2启动子活性，进而抑制了肺癌细胞的表型。本研究通过对BAI1基因的系列研究，阐明了其抑制肺癌细胞的分子生物学机制，揭示了BAI1在肺癌发展过程中的重要作用。