Upregulation of cystathionine-β-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis

Ches'Nique M. Phillips, John R. Zatarain, Michael E. Nicholls, Craig Porter, Steven Widen, Ketan Thanki, Paul Johnson, Muhammad U. Jawad, Mary P. Moyer, James W. Randall, Judith L. Hellmich, Manjit Maskey, Suimin Qiu, Thomas Wood, Nadiya Druzhyna, Bartosz Szczesny, Katalin Modis, Csaba Szabo, Celia Chao, Mark Hellmich

Research output: Contribution to journalArticle

15 Citations (Scopus)

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-tomesenchymal 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.

Original languageEnglish (US)
Pages (from-to)5741-5754
Number of pages14
JournalCancer Research
Volume77
Issue number21
DOIs
StatePublished - Nov 1 2017

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Cystathionine
Carcinogenesis
Up-Regulation
Epithelium
Genes
Transcriptome
Colorectal Neoplasms
Anoikis
Aberrant Crypt Foci
Gene Knockdown Techniques
Adenomatous Polyps
Pentose Phosphate Pathway
Hydrogen Sulfide
Lipogenesis
Sphingolipids
Mutagens
Glycolysis
Cadherins
Bile Acids and Salts
Cell Adhesion

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Upregulation of cystathionine-β-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis. / Phillips, Ches'Nique M.; Zatarain, John R.; Nicholls, Michael E.; Porter, Craig; Widen, Steven; Thanki, Ketan; Johnson, Paul; Jawad, Muhammad U.; Moyer, Mary P.; Randall, James W.; Hellmich, Judith L.; Maskey, Manjit; Qiu, Suimin; Wood, Thomas; Druzhyna, Nadiya; Szczesny, Bartosz; Modis, Katalin; Szabo, Csaba; Chao, Celia; Hellmich, Mark.

In: Cancer Research, Vol. 77, No. 21, 01.11.2017, p. 5741-5754.

Research output: Contribution to journalArticle

Phillips, CNM, Zatarain, JR, Nicholls, ME, Porter, C, Widen, S, Thanki, K, Johnson, P, Jawad, MU, Moyer, MP, Randall, JW, Hellmich, JL, Maskey, M, Qiu, S, Wood, T, Druzhyna, N, Szczesny, B, Modis, K, Szabo, C, Chao, C & Hellmich, M 2017, 'Upregulation of cystathionine-β-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis', Cancer Research, vol. 77, no. 21, pp. 5741-5754. https://doi.org/10.1158/0008-5472.CAN-16-3480
Phillips, Ches'Nique M. ; Zatarain, John R. ; Nicholls, Michael E. ; Porter, Craig ; Widen, Steven ; Thanki, Ketan ; Johnson, Paul ; Jawad, Muhammad U. ; Moyer, Mary P. ; Randall, James W. ; Hellmich, Judith L. ; Maskey, Manjit ; Qiu, Suimin ; Wood, Thomas ; Druzhyna, Nadiya ; Szczesny, Bartosz ; Modis, Katalin ; Szabo, Csaba ; Chao, Celia ; Hellmich, Mark. / Upregulation of cystathionine-β-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis. In: Cancer Research. 2017 ; Vol. 77, No. 21. pp. 5741-5754.
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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-tomesenchymal 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.",
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