PYGL重塑抑癌代谢酶FH的表观遗传修饰模式促进肾细胞癌进展的作用及分子机制研究

证据表明肾细胞癌（RCC）是一种代谢性疾病，糖原代谢异常在癌症发病机制中具有重要作用。前期研究中，我们利用高分辨率质谱技术结合自主研发的QDB技术发现糖原磷酸化酶PYGL在肾癌组织中高表达，体内、外研究证实敲低PYGL或小分子抑制剂均可抑制肾癌细胞生长，进一步研究发现敲低PYGL可激活肿瘤抑制因子FH并降低富马酸的累积，同时组蛋白甲基化水平升高，据此提出科学假设：PYGL可能通过重塑FH基因的表观修饰模式导致其失活促进肾癌的发生发展。本项目拟在细胞和动物水平通过代谢组学分析、hMeDIP-seq、ChIP等技术：1）阐明PYGL对表观遗传修饰模式的调控作用及分子机制；2）揭示PYGL调控FH表观修饰模式及功能的分子机制；3）探索PYGL通过调控FH酶活性在肾癌发生发展中的作用。本项目将系统阐述PYGL介导的糖原代谢在肾癌中发挥的分子调控网络，进一步丰富糖原代谢异常的致病机制。

Evidence suggests that renal cell carcinoma (RCC) is a metabolic disease and abnormal glycogen metabolism plays an important role in the pathogenesis of cancer. In previous studies, we found the high expression of glycogen phosphorylase PYGL in renal cancer tissues through high-resolution mass spectrometry combined with self-developed QDB technology. In vivo and vitro studies have confirmed that either PYGL knockdown or small molecule inhibitors can inhibit the growth of renal cancer cells and activate the tumor suppressor FH and reduce the accumulation of fumaric acid, and reduce the level of histone methylation. Therefore, it was hypothesized that PYGL might inactive FH gene to promote the occurrence and development of renal cancer by remodeling the epigenetic modification pattern of FH gene. This project will harness metabonomic, hMeDIP-seq, ChIP and other techniques at the cellular and animal levels to: 1) elucidate the role and molecular mechanism of PYGL effecting epigenetic modification patterns; 2) reveal the molecular mechanism of PYGL in regulating the epigenetic modification pattern and function of FH; 3) explore the role of PYGL in the development and progression of renal carcinoma by regulating FH enzyme activity. This project will systematically elaborate the molecular regulatory network that PYGL-mediated glycogen metabolism plays in renal cancer, and further enrich the pathogenic mechanism of abnormal glycogen metabolism.