The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer.
The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer.
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DOI：
10.1016/j.ebiom.2018.07.002
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发表时间：
2018-07
期刊：
影响因子：
11.1
通讯作者：
Relógio A
中科院分区：
文献类型：
--
作者：
Fuhr L;El-Athman R;Scrima R;Cela O;Carbone A;Knoop H;Li Y;Hoffmann K;Laukkanen MO;Corcione F;Steuer R;Meyer TF;Mazzoccoli G;Capitanio N;Relógio A
内源性分子发条驱动各种细胞途径，包括代谢和细胞周期。其失调能够促进病理表型，包括癌症。除了显著的代谢改变外，癌细胞还表现出时钟表型的严重变化，可能导致肿瘤进展和治疗反应。在这项研究中，我们使用一种全面的系统驱动的方法来研究生物钟中断对代谢途径的影响及其对结肠癌进展细胞模型中药物反应的影响。我们确定了原发性肿瘤及其转移性肿瘤的独特的时间相关转录组学和代谢特征。将表达数据映射到人类代谢的全面基因组规模重建，允许对24 h振荡转录物进行深入的功能表征，并指出肿瘤发生中的时钟驱动的代谢重编程。特别是，我们确定了一组五个时钟调控的糖酵解基因，ALDH3A2，ALDOC，HKDC1，PCK2和PDHB与差异的时间表达模式。这些发现在类器官和从同一患者的正常结肠和结肠腺癌分离的原代成纤维细胞中得到验证。我们进一步确定了HKDC 1与原发性肿瘤中的时钟的相互联系，该联系在转移性细胞中丢失。有趣的是，核心时钟基因BMAL1的破坏会影响HKDC1，并导致代谢的时间依赖性重新布线，即糖酵解活性增加以及治疗反应的变化。这项工作提供了新的证据，说明生物钟和代谢改变在癌症发生中的复杂相互作用，并确定了两个系统之间的新联系，这些系统在癌症进展和对治疗的反应中起着关键作用。来自同一患者的原发性和转移性结肠癌细胞显示出不同的时间依赖性代谢谱。生物钟的扰动诱导转录组水平的差异改变，包括代谢途径。核心时钟基因（BMAL1）敲除影响癌细胞的代谢活性并影响治疗反应。一个进化保守的分子时钟允许生物体通过驱动包括代谢和细胞周期在内的各种细胞途径来使生理和生物过程适应地球物理时间。除了显著的代谢改变外，癌细胞还显示出生物钟的严重变化，可能影响肿瘤进展和治疗反应。越来越多的努力已经阐明了昼夜节律钟电路，肿瘤进展和癌症相关的代谢改变之间的联系，但这种相互作用的更详细的知识仍然缺失。在这项研究中，我们研究了结肠癌进展的细胞模型和患者样本中独特的时间相关转录组学和代谢特征。我们发现，一个中断的生物钟导致改变基因表达，代谢重编程和药物反应的变化的时间概况，并确定己糖激酶HKDC 1在这方面的一个关键因素。我们的研究结果提供了新的证据，说明生物钟和代谢改变在癌症发生中的复杂相互作用，并为癌症治疗的可能优化铺平了道路。
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. Primary and metastatic colon cancer cells from the same patient show differential time-dependent metabolic profiles. Perturbations of the circadian clock induce differential alterations at the transcriptome level including metabolic pathways. Core-clock gene (BMAL1) knockdown affects metabolic activity of cancer cells and impinges on treatment response. An evolutionary conserved molecular clockwork allows organisms to adapt physiology and biological processes to the geophysical time by driving various cellular pathways including metabolism and the cell cycle. In addition to dramatic metabolic alterations, cancer cells show severe changes in the biological clock likely to affect tumor progression and treatment response. Increasing efforts have been made to elucidate the connection between the circadian clock circuitry, tumor progression and cancer-associated metabolic alterations, yet a more detailed knowledge of this interplay is still missing. In this study, we investigated distinctive time-related transcriptomic and metabolic features in a cellular model of colon cancer progression and patient samples. We show that a disrupted biological clock leads to altered temporal profiles of gene expression, metabolic reprogramming and changes in drug response, and identify the hexokinase HKDC1 as a crucial element in this connection. Our results provide novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and pave the way to a possible optimization of cancer treatment.
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影响因子：
46.9
作者：
通讯作者：
--
癌症发展和治疗中的生物钟。
DOI：
10.1016/b978-0-12-396971-2.00009-9
发表时间：
2013
影响因子：
--
作者：
Fu, Loning;Kettner, Nicole M.
通讯作者：
Kettner, Nicole M.
DOI：
10.1016/j.cbd.2007.11.002
发表时间：
2008-03-01
影响因子：
3
作者：
Irwin, David M.;Tan, Huanran
通讯作者：
Tan, Huanran
影响因子：
50.5
作者：
Giacchetti, S.;Dugue, P. A.;Levi, F.
通讯作者：
Levi, F.
影响因子：
4.3
作者：
Cammarota F;Laukkanen MO
通讯作者：
Laukkanen MO