PHF8调节HIF-CPT1A的分子机制及其在肾透明细胞癌脂质沉积中的作用

脂质沉积在ccRCC的恶性表型转化、抗血管治疗抵抗及肿瘤进展中发挥重要作用。最新研究表明CPT1A介导的脂肪酸氧化异常可能是ccRCC脂质沉积的重要原因，但调控CTP1A的具体机制尚不清楚。以往及我们的研究发现，HIFs可抑制CPT1A的表达，而敲低PHF8可逆转HIFs对CPT1A的转录抑制作用，从而减少脂质沉积，抑制ccRCC的进展。结合以往及我们前期的结果，我们推测：PHF8作为HIFs的转录共抑制因子，通过转录抑制CPT1A的表达促进脂质的沉积，在肾癌发生发展中发挥重要作用。本项目拟以基因编辑动物、裸鼠移植瘤和ccRCC细胞模型为研究对象，研究PHF8对HIF-CPT1A信号的调节机制及其在ccRCC脂质沉积和肿瘤进展中的作用。研究结果不仅有助于揭示ccRCC发生发展新的分子机制，而且为其治疗寻找新的靶向分子奠定基础，对提高ccRCC治疗效果具有重要科学意义及潜在的临床应用价值。

Multiple lines of evidences demonstrate that lipid deposition plays important roles in the progression and antiangiogenic drug resistance of ccRCC. Recent research has shown that the abnormalities of CPT1A-mediated fatty acid oxidation might be the major cause of the lipid deposition in ccRCC. However, the underlying molecular mechanism by which CPT1A was regulated still remains unclear. Our and others’ previous findings showed that HIFs could repress CPT1A expression; and PHF8 knockdown might reverse the transcriptional inhibitory effect of HIFs on CPT1A, subsequently inhibit the lipid deposition and tumor progression. Taken all together, we hypothesized that PHF8, as a co-repressor of HIFs, might play an important role in the lipid deposition and tumor progression of ccRCC by regulating CPT1A. In this study, by using gene editing mice, xenografts and ccRCC cell lines, we will investigate how PHF8 regulates the expressions of HIF-mediated CPT1A, as well as their effects on the lipid deposition and tumor progression of ccRCC. These studies will shed a new insight into understanding the molecular mechanisms underlying the lipid deposition and tumor progression of ccRCC, as well as looking for the potential molecular target for therapeutic intervention of ccRCC, which is of very important scientific significance as well as clinical value.