Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based a...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 37; pp. E7697 - E7706
Main Authors Satoh, Kiyotoshi, Yachida, Shinichi, Sugimoto, Masahiro, Oshima, Minoru, Nakagawa, Toshitaka, Akamoto, Shintaro, Tabata, Sho, Saitoh, Kaori, Kato, Keiko, Sato, Saya, Igarashi, Kaori, Aizawa, Yumi, Kajino-Sakamoto, Rie, Kojima, Yasushi, Fujishita, Teruaki, Enomoto, Ayame, Hirayama, Akiyoshi, Ishikawa, Takamasa, Taketo, Makoto Mark, Kushida, Yoshio, Haba, Reiji, Okano, Keiichi, Tomita, Masaru, Suzuki, Yasuyuki, Fukuda, Shinji, Aoki, Masahiro, Soga, Tomoyoshi
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 12.09.2017
SeriesPNAS Plus
Subjects
Aberration
Adenoma
Biological Sciences
Cancer
Cancer therapies
Carcinogenesis
Carcinogens
Colorectal cancer
Colorectal carcinoma
Deoxyribonucleic acid
DNA
DNA methylation
Evolution
Gene expression
Genes
Macromolecules
Metabolism
Mitochondria
Mutation
Myc protein
PNAS Plus
Studies
Tissues
Tumors
metabolism
colorectal cancer
omics
metabolomics
MYC
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Summary:Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.
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Author contributions: K. Satoh, S.Y., S.F., and T.S. designed research; K. Satoh, S.Y., M.O., T.N., S.A., S.T., K. Saitoh, K.K., S.S., K.I., Y.A., R.K.-S., Y. Kojima, T.F., A.H., T.I., Y. Kushida, R.H., K.O., M.T., M.A., and T.S. performed research; M.M.T. and Y.S. contributed new reagents/analytic tools; K. Satoh, S.Y., M.S., A.E., and T.S. analyzed data; and K. Satoh, S.Y., M.S., M.A., and T.S. wrote the paper.
Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, and approved August 9, 2017 (received for review June 9, 2017)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1710366114