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.
Highlights
Melanoma, a malignant tumor that arises from melanocytes, is the most dangerous skin tumor, displaying high recurrence and a low survival rate that contribute to more than 50,000 deaths per year worldwide
Consistent with the observations in patients, the survival time of FAHsilenced animals was longer than that of the control groups (Figure 1D). These results showed that high fumarylacetoacetate hydrolase (FAH) expression is common in melanoma and is associated with shortened survival times in both patients and tumorbearing mice
Anaplerotic reactions are essential for replenishing tricarboxylic acid (TCA) cycle intermediates; they maintain the homeostasis www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget of multiple metabolic pathways and are crucial for the survival and proliferation of tumor cells
Summary
A malignant tumor that arises from melanocytes, is the most dangerous skin tumor, displaying high recurrence and a low survival rate that contribute to more than 50,000 deaths per year worldwide. Increasing evidence suggests that metabolic reprogramming is a critical hallmark of tumor cells [1,2,3] This phenomenon is considered to be largely regulated by oncogenic activation, which might be linked to specific transcription factor activity, signal transduction pathways, and/or epigenetic mechanisms [4]. Www.impactjournals.com/oncotarget mounting evidence demonstrated that mitochondrial functions, albeit frequently dysregulated in cancer cells, play essential biosynthetic roles in various tumors, especially in melanoma, and contribute to metabolic reprogramming by enhancing anaplerotic reactions [10,11,12,13]. Anaplerotic flux must balance cataplerotic flux to maintain the homeostasis of multiple metabolic pathways, such as the TCA cycle, in normal tissues and in tumors such as melanoma [13, 17]
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