SETD1B通过竞争性调控CPT1A泛素化促进卵巢癌网膜转移的机制研究

卵巢癌对网膜具有特定的转移侵袭倾向，发生网膜转移的卵巢癌患者预后极差，而目前其机制尚不清楚。在前期研究中，本课题组首次在组织层面发现卵巢癌网膜转移灶中的脂肪酸氧化代谢速率明显增高，并证实脂肪酸氧化的关键限速酶CPT1A在卵巢癌细胞的转移侵袭过程中发挥重要调控作用。同时本课题组首次提出SETD1B与TRIM25竞争性调控CPT1A泛素化促进卵巢癌网膜转移的机制，并拟在前期研究基础上，综合临床标本、细胞与动物等研究模型揭示SETD1B异常活化→竞争性“占据”CPT1A蛋白的K441位点，促进K441位点的甲基化→TRIM25与CPT1A在K441位点结合受阻→CPT1A泛素化降解减少，蛋白水平升高→卵巢癌细胞脂肪酸氧化代谢增强→产生大量ATP为卵巢癌细胞供能→卵巢癌细胞增殖侵袭能力增强→卵巢癌网膜转移发生的机制，为拓展卵巢癌恶性生物学行为的研究方向及挖掘卵巢癌新的治疗靶点提供依据。

Ovarian cancer has a predilection for metastasis to omentum and patients with omental metastasis usually have very poor prognosis. However, the mechanism behind omental metastasis is still unknown. In this study, for the first time, we found that the rate of fatty acid oxidation in the omental metastasis of ovarian cancer was significantly higher than that in the primary tumor and non-omental metastasis in clinical samples. And we also confirmed that CPT1A, the key rate limiting enzyme of fatty acid oxidation, played a critical role in the process of metastasis and invasion of ovarian cancer cells. Moreover, our group initially found the mechanism that SETD1B and TRIM25 competitively regulate CPT1A ubiquitination, influencing omental metastasis of ovarian cancer. On the basis of previous study, we will integrate clinical samples, in vitro and in vivo experiment to reveal this regulation pathway: abnormally activated SETD1B competitively "occupies" and promotes the methylation of K441 on CPT1A protein, which hinders the binding of TRIM25 and CPT1A at K441 and decreases the ubiquitination and degradation of CPT1A, resulting in increased CPT1A protein level in ovarian cancer cells. Upregulated CPT1A protein level enhances fatty acid oxidation to produce a large amount of ATP and provide energy for ovarian cancer cells, thus increasing the proliferation and invasion ability of ovarian cancer as well as omental metastasis. This study will provide evidence for expanding the research filed in biological behavior of ovarian cancer and exploring new therapeutic targets of ovarian cancer.