PTEN半胱氨酸琥珀酰化修饰调节胶质母细胞瘤肿瘤形成的分子机制

胶质母细胞瘤是恶性程度最高的中枢神经系统肿瘤，常发生PTEN基因缺失或突变失活，导致PI3K/AKT信号通路激活从而促进肿瘤形成。然而，PTEN野生型胶质母细胞瘤中PI3K/AKT信号通路如何维持尚不明确。我们前期通过质谱检测发现PTEN存在一类从未报道的新翻译后修饰：半胱氨酸琥珀酰化。该修饰由代谢中间产物延胡索酸通过Michael加成反应加合到PTEN的半胱氨酸残基上直接产生。半胱氨酸琥珀酰化修饰可抑制PTEN活性，提高肿瘤细胞中PI3K/AKT信号通路水平。本项研究，我们将从蛋白质稳定性、细胞膜分布、脂质磷酸酶活性等方面探究半胱氨酸琥珀酰化如何影响PTEN对PI3K/AKT信号通路的调节，以及对胶质母细胞瘤肿瘤形成及预后的影响。本项目的顺利完成将有助于回答“胶质母细胞瘤如何克服野生型PTEN对肿瘤形成的阻遏作用”这一科学问题，为寻找针对PTEN野生型胶质母细胞瘤的治疗靶点提供理论基础。

Glioblastoma is the most malignant type of cancer in central nervous system. Monoallelic or complete deletion or somatic mutation of PTEN is frequently observed in glioblastoma, leading to activation of PI3K/AKT pathway and subsequently tumorigenesis. However, how to maintain PI3K/AKT pathway in PTEN widetype glioblastoma remains unclear. Recently, we identified a novel and unappreciated post-translational modification, cysteine-succination, on PTEN through mass spectrometry. This modification was achieved by directly adding fumarate onto cysteine residue of PTEN, whose reaction is called Michael addition. The cysteine-succination modification resulted in suppression of PTEN activity and activation of PI3K/AKT pathway in glioblastoma. In this study, we aim to investigate the mechanisms underlying cysteine-succination-suppressed PTEN activity by integral analysis of protein stability, cell membrane distribution, and lipid phosphatase activity of PTEN. We will also aim to illustrate the effect of PTEN cysteine-succination on tumorigenesis and prognosis of glioblastoma. The successful complete of this study will contribute to solve the key scientific question in glioblastoma, that is how to prevail PTEN’s negative effect on glioblastoma tumorigenesis. This study will also be beneficial for exploring new targets for treating PTEN widetype gliobloastomas.