Upregulation of Cystathionine-β-synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis
Phillips, Ches'Que Moquette
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Cystathionine β synthase (CBS) is a hydrogen sulfide producing enzyme that catalyzes the first step of the transsulfuration pathway converting homocysteine to cystathionine. CBS and the subsequent production of H2S are selectively upregulated in human colon cancer compared to patient matched normal margin mucosa. CBS produced H2S enhances cancer cell bioenergetics, tumor growth, proliferation, and angiogenesis. This dissertation focuses on whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report CBS expression upregulation begins in premalignant colonic specimens. Additionally, forced upregulation of CBS in an adenoma-like colonic epithelial cell line (NCM356) is sufficient to induce increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immunocompromised mice. CBS expression enhances cell bioenergetics and regulates cell metabolism, by inducing a metabolic reprogramming (anabolic metabolism) that is characterized by increased anaerobic glycolysis, pentose phosphate pathway signaling, lactate production, and ROS production. CBS upregulation induced broad changes in the NCM356 cell transcriptome with over 350 differentially expressed genes. These genes overlapped significantly with gene sets related to glycolysis, hypoxia, and a colon cancer cell phenotype, including genes regulated by NF-κB, KRAS, p53, and Wnt signaling, genes downregulated after E-cadherin knockdown, and genes related to increased extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis.