Upregulation of Cystathionine-β-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis
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Abstract
The trans-sulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differentially expressed metabolites (65 increased and 20 decreased) clustered into the glycolytic pathway, nucleotide sugars, intermediates of the pentose phosphate pathway, and lipogenesis, including primarily phospholipids, sphingolipids, and bile acids. 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. The CBS-induced switch to an anabolic metabolism was associated with increased NCM356 cell bioenergetics, proliferation, invasion through Matrigel, resistance to anoikis, and CBS-dependent tumorigenesis in immunocompromised mice. Genetic ablation of CBS in CBS heterozygous mice (CBS+/−) reduced the number of mutagen-induced aberrant colonic crypt foci. Taken together, these results establish that activation of the CBS/H2S axis promotes colon carcinogenesis. Cancer Res; 77(21); 5741–54. ©2017 AACR.
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Metabolic changes occur in premalignant colonic polyps in humans and mice, and some are retained in adenocarcinomas.
“Other studies in humans and mice report metabolic changes in premalignant colonic polyps, some of which are retained in adenocarcinomas (21, 22).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [22]
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- Authors
- Phillips, C. M., Zatarain, J. R., Nicholls, M. E., Porter, C., Widen, S. G., Thanki, K., Johnson, P., Jawad, M. U., Moyer, M. P., Randall, J. W., Hellmich, J. L., Maskey, M., Qiu, S., Wood, T. G., Druzhyna, N., Szczesny, B., Módis, K., Szabo, C., Chao, C., & Hellmich, M. R.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Incell Corporation (United States) (US)
- 2Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas.
- Corresponding author
- Chao, Celia
- Hellmich, Mark R.
- ORCID
- Venue
- Cancer Research
- Published
- 2017-10-31
- Volume
- 77
- Issue
- 21
- Pages
- 5741-5754
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5668191
- OpenAlex
- W2754689486
- Cited by
- 139
- References
- 42
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 13 · 2023: 20 · 2022: 32 · 2021: 19 · 2020: 13 · 2019: 12 · 2018: 10 · 2017: 1
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 CA175803, T32 DK007639, UL1 TR001439, CPRIT DP150074, SHC 84090)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- cystathionine beta-synthase, hydrogen sulfide, colorectal carcinogenesis, colonic epithelium, adenomatous polyps, metabolic reprogramming, glycolysis, pentose phosphate pathway, lipogenesis, sphingolipids, bile acids, epithelial-mesenchymal transition, NF-κB signaling, Wnt signaling, KRAS, p53, E-cadherin, anoikis resistance, tumor invasion, aberrant crypt foci
- MeSH terms
- Animals, Cell Line, Cell Movement, Colon, Cystathionine beta-Synthase, Female, Humans, Hydrogen Sulfide, Intestinal Mucosa, Male, Mice, Nude, Transplantation, Heterologous, Up-Regulation, Gene Expression Regulation, Neoplastic, Adenomatous Polyps, Mice, Knockout, Gene Expression Profiling, HCT116 Cells, Metabolomics, Carcinogenesis
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