The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer

Luise Fuhr, Rukeia El-Athman, Rosella Scrima, Olga Cela, Annalucia Carbone, Henning Knoop, Yin Li, Karen Hoffmann, Mikko O. Laukkanen, Francesco Corcione, Ralf Steuer, Thomas F. Meyer, Gianluigi Mazzoccoli, Nazzareno Capitanio, Angela Relógio

Research output: Contribution to journalArticle

Abstract

An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock–regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy.

Original languageEnglish
Pages (from-to)105-121
Number of pages17
JournalEBioMedicine
Volume33
DOIs
Publication statusPublished - Jul 1 2018

Keywords

  • Circadian clock
  • Circadian regulation of metabolism
  • Colorectal cancer
  • Glycolysis
  • High-throughput circadian data
  • Metabolic network reconstruction
  • Metabolic rewiring
  • Treatment response
  • Tumor progression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Fuhr, L., El-Athman, R., Scrima, R., Cela, O., Carbone, A., Knoop, H., Li, Y., Hoffmann, K., Laukkanen, M. O., Corcione, F., Steuer, R., Meyer, T. F., Mazzoccoli, G., Capitanio, N., & Relógio, A. (2018). The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer. EBioMedicine, 33, 105-121. https://doi.org/10.1016/j.ebiom.2018.07.002