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

EBioMedicine
Luise FuhrAngela Relógio

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 sa...Continue Reading

Citations

Jan 24, 2019·IUBMB Life·Kate DavisPauline J van der Watt
Jun 15, 2019·International Journal of Molecular Sciences·Consiglia PacelliNazzareno Capitanio
May 18, 2019·British Journal of Pharmacology·Laetitia S GasparCláudia Cavadas
Sep 26, 2019·Chembiochem : a European Journal of Chemical Biology·Elena S Reckzeh, Herbert Waldmann
Aug 25, 2019·International Journal of Molecular Sciences·Rukeia El-AthmanAngela Relógio
Aug 6, 2019·Frontiers in Endocrinology·Urša KovačTadeja Režen
Jun 15, 2019·Genome Biology·Changdai GuSang Yup Lee
Apr 29, 2020·Cell Death & Disease·Alessia ParascandoloMikko O Laukkanen
Jun 15, 2020·Biochemical and Biophysical Research Communications·Tadeja ReženDamjana Rozman
Jul 8, 2021·Current Diabetes Reports·Joseph L ZapaterBrian T Layden
Aug 28, 2021·Biomedicines·María I Aroca-SiendonesJosefa León
Aug 9, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Rosella ScrimaNazzareno Capitanio

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Datasets Mentioned

BETA
E-MTAB-5876

Methods Mentioned

BETA
transfection
Assay
PCR
electrophoresis

Key Resources (RRID) Mentioned

AB_148468
CVCL_0547
CVCL_0027
CVCL_0063

Software Mentioned

Mfuzz
ConsensusPathDB
Chronostar
RAIN
ImageJ Lab
R package
RECON
R package HarmonicRegression

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