Abstract
High-grade serous (HGS) ovarian cancer accounts for 90% of all ovarian cancer-related deaths. However, factors that drive HGS ovarian cancer tumor growth have not been fully elucidated. In particular, comprehensive analysis of the metabolic requirements of ovarian cancer tumor growth has not been performed. By analyzing The Cancer Genome Atlas mRNA expression data for HGS ovarian cancer patient samples, we observed that six enzymes of the folic acid metabolic pathway were overexpressed in HGS ovarian cancer samples compared with normal ovary samples. Systematic knockdown of all six genes using short hairpin RNAs (shRNAs) and follow-up functional studies demonstrated that serine hydroxymethyl transferase 1 (SHMT1) was necessary for ovarian cancer tumor growth and cell migration in culture and tumor formation in mice. SHMT1 promoter analysis identified transcription factor Wilms tumor 1 (WT1) binding sites, and WT1 knockdown resulted in reduced SHMT1 transcription in ovarian cancer cells. Unbiased large-scale metabolomic analysis and transcriptome-wide mRNA expression profiling identified reduced levels of several metabolites of the amino sugar and nucleotide sugar metabolic pathways, including sialic acid N-acetylneuraminic acid (Neu5Ac), and downregulation of pro-oncogenic cytokines interleukin-6 and 8 (IL-6 and IL-8) as unexpected outcomes of SHMT1 loss. Overexpression of either IL-6 or IL-8 partially rescued SHMT1 loss-induced tumor growth inhibition and migration. Supplementation of culture medium with Neu5Ac stimulated expression of IL-6 and IL-8 and rescued the tumor growth and migratory phenotypes of ovarian cancer cells expressing SHMT1 shRNAs. In agreement with the ovarian tumor-promoting role of Neu5Ac, treatment with Neu5Ac-targeting glycomimetic P-3Fax-Neu5Ac blocked ovarian cancer growth and migration. Collectively, these results demonstrate that SHMT1 controls the expression of pro-oncogenic inflammatory cytokines by regulating sialic acid Neu5Ac to promote ovarian cancer tumor growth and migration. Thus, targeting of SHMT1 and Neu5Ac represents a precision therapy opportunity for effective HGS ovarian cancer treatment.
Highlights
According to the most recent estimates, ~ 22 280 new cases of ovarian cancer will be diagnosed and 14 240 women will die of this disease in the United States this year alone.[1]
To identify metabolic alterations that are necessary for ovarian cancer tumor growth, we analyzed the The Cancer Genome Atlas (TCGA) gene expression data from 489 ovarian cancer samples and found that multiple genes encoding the enzymes for oxidative phosphorylation, histidineglutamate-glutamine metabolism and folic acid metabolism were significantly upregulated in ovarian cancer samples compared with the normal ovary control (Supplementary Figure 1)
To determine whether any of these genes were necessary for ovarian cancer tumor growth, we knocked down each gene individually in the ovarian cancer cell line PEO4 using genespecific short hairpin RNAs (Supplementary Figure 3A)
Summary
According to the most recent estimates, ~ 22 280 new cases of ovarian cancer will be diagnosed and 14 240 women will die of this disease in the United States this year alone.[1]. 316 of these tumors were analyzed by exome sequencing to identify mutations These studies identified recurrent mutations in 10 genes, focal copy number alterations in 113 genes and promoter methylation alterations of 168 genes, and captured transcriptional alterations in ovarian cancer samples compared with normal ovary samples.[3] not many actionable alterations of therapeutic value for ovarian cancer patients have been identified far. This is, in part, due to the lack of functional studies to determine which of these alterations identified by the TCGA studies have decisive roles in promoting ovarian cancer tumor growth and progression
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