CDC5L drives FAH expression to promote metabolic reprogramming in melanoma
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Zhichao Gu1, Huafeng Zhang2, Yong Li3, Susu Shen1, Xiaonan Yin4, Wei Zhang1, Ruimin Cheng1, Yong Zhang1, Xiaoyan Zhang1, Hui Chen1, Bo Huang4 and Yuchun Cao1
1Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
3Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
4National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
Yuchun Cao, email: [email protected]
Keywords: fumarylacetoacetate hydrolase (FAH); anaplerotic reactions; cell division cycle 5-like protein (CDC5L); tumor metabolic reprogramming; melanoma
Received: August 09, 2017 Accepted: November 15, 2017 Published: December 07, 2017
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 13C 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.
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