Analysis of the Circadian Regulation of Cancer Hallmarks by a Cross-Platform Study of Colorectal Cancer Time-Series Data Reveals an Association with Genes Involved in Huntington’s Disease

Abstract

Accumulating evidence points to a link between circadian clock dysfunction and the molecular events that drive tumorigenesis. Here, we investigated the connection between the circadian clock and the hallmarks of cancer in an in vitro model of colorectal cancer (CRC). We used a cross-platform data normalization method to concatenate and compare available microarray and RNA-sequencing time series data of CRC cell lines derived from the same patient at different disease stages. Our data analysis suggests differential regulation of molecular pathways between the CRC cells and identifies several of the circadian and likely clock-controlled genes (CCGs) as cancer hallmarks and circadian drug targets. Notably, we found links of the CCGs to Huntington’s disease (HD) in the metastasis-derived cells. We then investigated the impact of perturbations of our candidate genes in a cohort of 439 patients with colon adenocarcinoma retrieved from the Cancer Genome Atlas (TCGA). The analysis revealed a correlation of the differential expression levels of the candidate genes with the survival of patients. Thus, our study provides a bioinformatics workflow that allows for a comprehensive analysis of circadian properties at different stages of colorectal cancer, and identifies a new association between cancer and HD.

An Optimal Time for Treatment—Predicting Circadian Time by Machine Learning and Mathematical Modelling

“…While a general prediction of optimal irinotecan timing can be based on cell lines [ 198 , 199 ], the prediction could potentially be improved by personalized transcription-translational networks. A personalized cancer-specific model of the core-clock should for example include the mutations in core-clock genes seen in around 4% of cancer patients [ 44 ]. Besides the irinotecan network, the addition of a cell-cycle network could be interesting for treatment by timing medication to the cell cycle of non-cancer cells, which likely have a different clock [ 25 ].…”

“…Given the range of molecular time-dependent processes that the circadian clock regulates, including metabolism, DNA repair and the cell cycle, it has the potential to act as a tumor suppressor [ 25 , 46 ]. Indeed, several clock-controlled genes show a strong association with cancer and cancer progression, in particular genes related to metabolism [ 26 , 28 , 44 ]. In reverse, cancer also impacts the core-clock network [ 48 ], which, when implemented into a combined model, will result in a complex interaction between the core-clock and the cancer network.…”

“…Due to its function as regulator of physiology and behavior in synchrony with external environmental cues, the circadian machinery is responsible for generating and maintaining proper organ functionality, via regulating gene and protein activity. In fact, studies conducted in animal models including mice [ 42 ] and the primate Papio anubis (baboon, [ 43 ]) reported that more than 80% of protein-coding genes show circadian rhythms in expression, in at least one tissue and several of these genes are involved in processes related to the so-called hallmarks of cancer [ 44 ]. These include genes governing key biological functions such as energy metabolism (e.g., NR1D1 , HKDC1 , PCK1 and GLUTs ), DNA repair (e.g., XPA and TP53 ), cell cycle (e.g., MYC , WEE1 and INK4A ), cell motility (e.g., NR1D1 and SNAI1) , as well as protein and macromolecules integrity (e.g., KRT1 , ITM2B ) [ 25 , 28 , 42 , 43 , 45 , 46 , 47 , 48 ].…”

The role of the circadian clock in cancer hallmark acquisition and immune-based cancer therapeutics

“…In the following sections, we synthesize the emerging [3] or mutation [4] upregulates MYC in vivo, knockout increases cellular senescence in vivo [5] 2. Knockdown upregulates cyclin D1 expression in vitro [6], downregulation accelerates cell cycling in vitro [7] 3. Downregulation decreases apoptosis in vitro [7], knockout permits uncontrolled Atg14-mediated initiation of autophagy in vivo [8] 4.…”

Circadian Dysregulation of the TGFβ/SMAD4 Pathway Modulates Metastatic Properties and Cell Fate Decisions in Pancreatic Cancer Cells

“…This core-clock network (CCN) generates endogenous 24-h oscillations in the expression of genes and proteins and is involved in the circadian regulation of various cellular processes, including the cell cycle ( El-Athman et al., 2017 ), apoptosis ( Gery et al., 2005 ; Wang et al., 2016 ), DNA repair ( Di Micco et al., 2011 ), the epithelial-to-mesenchymal transition (EMT) ( Mao et al., 2012 ), metabolism ( Fuhr et al., 2018 ; Reinke and Asher, 2019 ), and immunity ( Abreu et al., 2018 ). Its aberrant function impacts cell functioning and can lead to the development and progression of several diseases including cancer ( Davis et al., 2019 ; Sulli et al., 2019 ; Yalcin et al., 2020 ). Genes involved in cell cycle regulation (e.g., MYC , WEE1, and INK4A ), immune function (e.g., TNF ), and metabolism (e.g., SIRT3 , CPT1, and PDH ) show a rhythmic pattern of expression and are known clock-controlled genes (CCGs).…”