组蛋白去甲基化酶PHF8调控线粒体稳态和细胞能量代谢的功能和分子机制研究

PHF8 is a histone demethylase, which contains PHD zinc finger and JmjC domains. Mutations in PHF8 have been found in patients with X-linked mental retardation (XLMR), and its over-expression has been seen in many different cancer types. However, the molecular mechanisms underlying PHF8 regulation of cancer development remain incompletely understood. Aberrant energy metabolism is one of the hallmarks of cancers. Our preliminary data suggested that, when mTOR was highly active in cells, PHF8 repressed the transcription of mitochondrial respiratory chain complex and mitochondrial translation genes，which was tightly linked to its functional partner YY1. Therefore, the current proposed study will focus on investigating the molecular mechanisms through which PHF8 and YY1 sense cellular energy and repress gene transcription, maintaining mitochondrial homeostasis and cellular energy metabolism. We will also investigate the implication of such mechanisms in cancer development, such as kidney renal papillary cell carcinoma (KIRP). We aim to establish a regulatory axis composed of mTOR, PHF8 and YY1, gene transcriptional repression and cancer development, with PHF8/YY1 at its center. Finally, screening and optimization of small molecules targeting PHF8 enzymatic activity or the interaction between PHF8 and YY1, and further validation of their efficacy and specificity will be done by using cell- and animal-based cancer models. To summarize, our ultimate goal is to reveal the molecular mechanisms underlying PHF8 regulation of cancer, which could be potentially serving as a drug target for the prevention and treatment of cancer.

PHF8是一个含有PHD锌指和Jumonji C（JmjC）结构域的组蛋白去甲基化酶。PHF8突变与X-连锁智力迟缓综合症密切相关，其过表达也被报道和多种癌症密切相关，但其作用分子机制不甚明确。能量代谢的失调是癌症的重要特征之一。我们前期研究表明细胞内mTOR处于高活性状态下，PHF8抑制线粒体呼吸链复合体和线粒体翻译功能相关基因的转录，并且这种功能和其结合的转录因子YY1密切相关。基于此，本项目将集中研究PHF8/YY1功能性复合物感知能量水平，抑制基因转录，从而调控线粒体稳态和细胞能量代谢的分子机制，及其该分子机制在肿瘤发生发展中的应用。建立一条mTOR/PHF8/YY1---基因转录抑制---癌症发生发展的分子通道。项目后期将针对PHF8酶活性或者PHF8/YY1相互作用进行活性小分子筛选，并通过细胞和动物实验验证其有效性和特异性，为将来的药物开发奠定基础。

能量代谢失调是癌症的重要标志性特征之一。PHF8是一个含有PHD锌指和Jumonji C（JmjC）结构域的蛋白去甲基化酶，其过度表达被报道与多种癌症的发生发展密切相关，但其作用的分子机制还不完全清楚。本项目主要研究PHF8调控能量代谢参与癌症发生发展的功能和分子机制。在本项目中，我们发现PHF8在多种类型的癌症中异常过度表达，与线粒体电子呼吸链复合体（ETC）亚基的基因表达水平显著性负相关。在肿瘤细胞中异常高度表达的PHF8可以结合并去甲基化修饰转录因子YY1调控其染色质结合，从而抑制细胞核编码的线粒体电子呼吸链复合体基因转录、上调肿瘤细胞内线粒体活性氧水平，这种能量代谢异常导致的氧化应激最终推动了癌症的发生发展。此外，本项目也开发了靶向PHF8的干预小分子，证实该小分子可调节PHF8底物甲基化水平、ETC基因转录、线粒体氧化应激和多种PHF8临床相关癌症类型的肿瘤细胞增殖，利用细胞系和患者来源异种移植瘤生长实验初步证实了该干预分子的体内有效性和安全性。总体上，本项目的研究揭示了癌症细胞中线粒体ETC基因转录的一个表观遗传调控机制，表明靶向蛋白去甲基化酶PHF8具有治疗临床相关癌症的潜在应用价值。