Protein Sialylation Regulates a Gene Expression Signature that Promotes Breast Cancer Cell Pathogenicity

Many mechanisms have been proposed for how heightened aerobic glycolytic metabolism fuels cancer pathogenicity, but there are still many unexplored pathways. Here, we have performed metabolomic profiling to map glucose incorporation into metabolic pathways upon transformation of mammary epithelial cells by 11 commonly mutated human oncogenes. We show that transformation of mammary epithelial cells by oncogenic stimuli commonly shunts glucose-derived carbons into synthesis of sialic acid, a hexosamine pathway metabolite that is converted to CMP-sialic acid by cytidine monophosphate <i>N</i>-acetylneuraminic acid synthase (CMAS) as a precursor to glycoprotein and glycolipid sialylation. We show that CMAS knockdown leads to elevations in intracellular sialic acid levels, a depletion of cellular sialylation, and alterations in the expression of many cancer-relevant genes to impair breast cancer pathogenicity. Our study reveals the heretofore unrecognized role of sialic acid metabolism and protein sialylation in regulating the expression of genes that maintain breast cancer pathogenicity

Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer

Targeting dysregulated metabolic pathways is a promising therapeutic strategy for eradicating cancer. Understanding how frequently altered oncogenes regulate metabolic enzyme targets would be useful in identifying both broad-spectrum and targeted metabolic therapies for cancer. Here, we used activity-based protein profiling to identify serine hydrolase activities that were consistently upregulated by various human oncogenes. Through this profiling effort, we found oncogenic regulatory mechanisms for several cancer-relevant serine hydrolases and discovered that platelet activating factor acetylhydrolase 1B2 and 1B3 (PAFAH1B2 and PAFAH1B3) activities were consistently upregulated by several oncogenes, alongside previously discovered cancer-relevant hydrolases fatty acid synthase and monoacylglycerol lipase. While we previously showed that PAFAH1B2 and 1B3 were important in breast cancer, our most recent profiling studies have revealed that these enzymes may be dysregulated broadly across many types of cancers. Here, we find that pharmacological blockade of both enzymes impairs cancer pathogenicity across multiple different types of cancer cells, including breast, ovarian, melanoma, and prostate cancer. We also show that pharmacological blockade of PAFAH1B2 and 1B3 causes unique changes in lipid metabolism, including heightened levels of tumor-suppressing lipids. Our results reveal oncogenic regulatory mechanisms of several cancer-relevant serine hydrolases using activity-based protein profiling, and we show that PAFAH1B2 and 1B3 are important in maintaining cancer pathogenicity across a wide spectrum of cancer types

Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer

Targeting dysregulated metabolic pathways is a promising therapeutic strategy for eradicating cancer. Understanding how frequently altered oncogenes regulate metabolic enzyme targets would be useful in identifying both broad-spectrum and targeted metabolic therapies for cancer. Here, we used activity-based protein profiling to identify serine hydrolase activities that were consistently upregulated by various human oncogenes. Through this profiling effort, we found oncogenic regulatory mechanisms for several cancer-relevant serine hydrolases and discovered that platelet activating factor acetylhydrolase 1B2 and 1B3 (PAFAH1B2 and PAFAH1B3) activities were consistently upregulated by several oncogenes, alongside previously discovered cancer-relevant hydrolases fatty acid synthase and monoacylglycerol lipase. While we previously showed that PAFAH1B2 and 1B3 were important in breast cancer, our most recent profiling studies have revealed that these enzymes may be dysregulated broadly across many types of cancers. Here, we find that pharmacological blockade of both enzymes impairs cancer pathogenicity across multiple different types of cancer cells, including breast, ovarian, melanoma, and prostate cancer. We also show that pharmacological blockade of PAFAH1B2 and 1B3 causes unique changes in lipid metabolism, including heightened levels of tumor-suppressing lipids. Our results reveal oncogenic regulatory mechanisms of several cancer-relevant serine hydrolases using activity-based protein profiling, and we show that PAFAH1B2 and 1B3 are important in maintaining cancer pathogenicity across a wide spectrum of cancer types