LncRNA TPT1-AS1/CBP/ATIC信号轴介导的嘌呤代谢紊乱调控乳腺癌恶性进展的机制研究

嘌呤代谢通路的异常激活在乳腺肿瘤进展过程中起到重要作用。长链非编码RNA在乳腺癌嘌呤代谢过程中的作用及机制尚不明确。本项目前期通过大数据分析发现LncRNA TPT1-AS1(TPT1-AS1)在乳腺癌组织中表达降低，同时功能学实验证明TPT1-AS1能够抑制乳腺癌细胞的增殖、转移及干细胞特性等恶性表型。质谱分析的结果发现TPT1-AS1敲除的乳腺肿瘤细胞嘌呤代谢通路被激活，且从头合成终产物IMP（肌苷酸）表达水平上升显著。进一步机制研究发现催化生成IMP的激酶ATIC表达受到TPT1-AS1的抑制作用，TPT1-AS1与CBP（CREB结合蛋白）蛋白结合导致ATIC启动子区组蛋白乙酰化水平降低，ATIC表达水平下降，最终肿瘤嘌呤代谢通路受阻，乳腺癌恶性表型受到抑制。本研究将通过对这一假说的验证，更加精细的揭示非编码RNA调控乳腺癌细胞生物学功能的分子机制，并为乳腺癌的治疗提供可能的靶点。

Purine biosynthetic pathway was recently identified to play crucial role in breast cancer progression. However, little was known about the regulatory mechanisms of long non-coding RNA in breast cancer purine metabolism. In this study, we found LncRNA TPT1-AS1 downregulated in breast cancer tissues by analyzing TCGA database. Functional studies showed that TPT1-AS1 inhibited breast cancer cell proliferation, invasion and stemness properties. Mass spectrometric analysis showed that purine biosynthetic pathway was activated in TPT1-AS1-knockdown MCF-7 cells and inosine monophosphate (IMP), the product of de novo purine biosynthesis was markedly upregulated. Mechanistically, we found that TPT1-AS1 could physically interact with CBP(CREB-binding protein), which consequently led to the loss of H3K27Ac in the enhancer of ATIC, the catalytic enzyme of IMP. This process would finally lead to the blockage of breast cancer purine metabolism and the inhibition of breast cancer progression. Our findings will illustrate the function of non-coding RNAs in reprograming breast cancer purine metabolism and provide a potential candidate for breast cancer therapy.