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CDC5L drives FAH expression to promote metabolic reprogramming in melanoma.


ABSTRACT: 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.

SUBMITTER: Gu Z 

PROVIDER: S-EPMC5768407 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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CDC5L drives FAH expression to promote metabolic reprogramming in melanoma.

Gu Zhichao Z   Zhang Huafeng H   Li Yong Y   Shen Susu S   Yin Xiaonan X   Zhang Wei W   Cheng Ruimin R   Zhang Yong Y   Zhang Xiaoyan X   Chen Hui H   Huang Bo B   Cao Yuchun Y  

Oncotarget 20171207 69


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 <sup>13</s  ...[more]

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