AHCYL1感知腺苷高半胱氨酸的分子机制及其在结直肠癌中的作用

Clinical evidences show that expression of Adenosylhomocysteinase Like 1 (AHCYL1) is a favorable prognostic marker and the 5-year survival rate of patients with higher expression levels was 71% compared with 43% survival for patients with lower expression, indicating inhibition of tumor growth by AHCYL1 in colorectal cancer (CRC). Previous study has showed that accumulation of S-Adenosyl-homocysteine (SAH) inhibits methyltransferases and causes methylation disorders; inhibition of class III PI 3-kinase (PIK3C3) induces cytokinesis arrest and an increase of multinucleate cells, resulting in apoptosis. We found AHCYL1 bound with PIK3C3 during cell division, which was dependent on phosphorylation. Additionally, SAH enhanced the interaction dramatically. We hypothesis that AHCYL1 is a metabolic checkpoint of cell cycle and senses SAH, avoiding daughter cells with unusual methylation through PIK3C3 inhibition and maintaining tissue homeostasis. Therefore, we will manipulate SAH concentration and AHCYL1 expression in cells to uncover the mechanism of sensing SAH by AHCYL1 and the role of AHCYL1 in tumorigenesis. Based on the new trend of sensing metabolite, our research will discover the underlying mechanisms of CRC tumorigenesis and provide a potential target for CRC therapy.

类腺苷高半胱氨酸酶（AHCYL1）高表达的结直肠癌患者五年生存率（71%）远高于低表达患者（43%），提示AHCYL1可能具有抑制肿瘤生长的作用。研究表明胞内腺苷高半胱氨酸(SAH)的积累会抑制甲基转移酶，导致甲基化水平紊乱，进而引发疾病；在细胞分裂期抑制PIK3C3（III型PI3K）会阻断胞质分裂，产生多核细胞引起凋亡。我们前期工作发现，磷酸化修饰的AHCYL1可与PIK3C3结合，并且该磷酸化修饰主要发生在细胞分裂期，同时SAH能显著促进二者的结合。我们推测AHCYL1作为细胞周期的代谢物检查点，在分裂期感知SAH浓度，通过抑制PIK3C3，诱导细胞多核化并凋亡，避免产生甲基化失调的子细胞，维持机体稳态。我们将系统研究AHCYL1感受SAH浓度的分子机制，从细胞感知代谢物的新角度阐明AHCYL1在肿瘤发生发展中的作用，探讨AHCYL1和SAH作为治疗结直肠癌靶点的可能。

自噬是细胞应对营养缺乏的主要途径，同时也是MTOR信号通路调控的主要生物学过程之一。SAM（S-腺苷甲硫氨酸）是细胞内最主要的甲基供体，而SAH（S-腺苷同型半胱氨酸）则是SAM在甲基转移反应过程中的代谢产物。由于SAH和SAM结构非常类似，SAH对所有依赖于SAM的甲基转移酶具有很强的抑制作用。.研究发现代谢物SAH通过AHCYL1（adenosylhomocysteinase like 1，类腺苷高半胱氨酸酶）抑制细胞自噬，并且该调控过程不依赖于经典的MTOR信号通路。AHCYL1作为代谢物SAH的感受器（sensor），随着胞内SAH浓度的升高，AHCYL1和PIK3C3（Ⅲ型磷脂酰肌醇-3激酶）的结合增强并抑制其激酶活性，进一步阻碍了PIK3C3调控的自噬起始过程。该调控机制在细胞以及斑马鱼中都得到了证实。.该研究发现了代谢物SAH的感受器AHCYL1，阐明了SAH除了作为代谢中间产物之外，还能够通过AHCYL1调控自噬等生物学过程。该发现不仅拓展了对细胞感知代谢物的认识，而且丰富了SAH的生物学功能。