TY - JOUR
T1 - Upregulation of cystathionine-β-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis
AU - Phillips, Ches'Nique M.
AU - Zatarain, John R.
AU - Nicholls, Michael E.
AU - Porter, Craig
AU - Widen, Steve G.
AU - Thanki, Ketan
AU - Johnson, Paul
AU - Jawad, Muhammad U.
AU - Moyer, Mary P.
AU - Randall, James W.
AU - Hellmich, Judith L.
AU - Maskey, Manjit
AU - Qiu, Suimin
AU - Wood, Thomas G.
AU - Druzhyna, Nadiya
AU - Szczesny, Bartosz
AU - Módis, Katalin
AU - Szabo, Csaba
AU - Chao, Celia
AU - Hellmich, Mark R.
N1 - Funding Information:
This work was supported by grants from the NIH, Cancer Prevention Research Institute of Texas, and Shriners Hospital for Children (R01 CA175803, T32 DK007639, UL1 TR001439, CPRIT DP150074, and SHC 84090).
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85035037004&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85035037004&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-3480
DO - 10.1158/0008-5472.CAN-16-3480
M3 - Article
C2 - 28923859
AN - SCOPUS:85035037004
SN - 0008-5472
VL - 77
SP - 5741
EP - 5754
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -