Gu Zhichao, Zhang Huafeng, Li Yong, Shen Susu, Yin Xiaonan, Zhang Wei, Cheng Ruimin, Zhang Yong, Zhang Xiaoyan, Chen Hui, Huang Bo, Cao Yuchun
Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Oncotarget. 2017 Dec 7;8(69):114328-114343. doi: 10.18632/oncotarget.23107. eCollection 2017 Dec 26.
Metabolic reprogramming allows tumor cells to thrive in the typically hypoxic tumor microenvironment. Using immunodetection and clinical data analyses, we demonstrate here that fumarylacetoacetate hydrolase (FAH) is highly expressed in melanoma and correlates with poor survival. FAH knockdown inhibits proliferation and migration, while promoting apoptosis in melanoma cells, result in prolonged survival in tumor-bearing mice. Molecular analyses using real time RT-PCR, western blot, and C tracing showed that these changes are driven by strong stimulation of anaplerotic reactions through the TCA cycle and the pentose-phosphate pathway, resulting in increased fatty acid and nucleotide synthesis. Using bioinformatic, ChIP-PCR, and gene silencing analyses, we determined that cell division cycle 5-like protein (CDC5L) is an important transcription factor regulating FAH expression in melanoma cells. These findings reveal that FAH induces metabolic reprogramming in melanoma and so emerges as both a potentially useful independent prognostic indicator and an attractive therapeutic target.
代谢重编程使肿瘤细胞能够在典型的缺氧肿瘤微环境中茁壮成长。通过免疫检测和临床数据分析，我们在此证明富马酰乙酰乙酸水解酶（FAH）在黑色素瘤中高表达，且与不良生存相关。敲低FAH可抑制黑色素瘤细胞的增殖和迁移，同时促进其凋亡，从而延长荷瘤小鼠的生存期。使用实时RT-PCR、蛋白质印迹和C追踪进行的分子分析表明，这些变化是由通过三羧酸循环（TCA循环）和磷酸戊糖途径对回补反应的强烈刺激所驱动的，导致脂肪酸和核苷酸合成增加。通过生物信息学、染色质免疫沉淀PCR（ChIP-PCR）和基因沉默分析，我们确定细胞分裂周期5样蛋白（CDC5L）是调节黑色素瘤细胞中FAH表达的重要转录因子。这些发现揭示了FAH在黑色素瘤中诱导代谢重编程，因此它既是一个潜在有用的独立预后指标，也是一个有吸引力的治疗靶点。
