Ras-Mediated Deregulation of the Circadian Clock in Cancer

Abstract

Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.

PARP1- and CTCF-Mediated Interactions between Active and Repressed Chromatin at the Lamina Promote Oscillating Transcription

“…Because the circadian rhythm of hESCs could not be synchronized (data not shown; Yagita et al, 2010) and the heterogeneous composition of hEBs (Experimental Procedures) compromised interpretation, we turned to HCT116 cells. These cells display circadian gene expression (Reló gio et al, 2014) and significant amplitude in the oscillating transcription of a circadian chromatin hub of the 4C network, PARD3, upon serum shock ( Figures S4A and S4B). Given the role of CTCF and PARP1 in the interactions between LADs and circadian genes, we first examined CTCF-PARP1 proximities during the circadian cycle.…”

The small G protein RAS2 is involved in the metabolic compensation of the circadian clock in the circadian model Neurospora crassa

“…In mice, the dexamethasone-induced RAS protein 1 (DEXRAS1) is suggested to be an input factor of the circadian clock (49)(50)(51)(52). Both experimental data and bioinformatic analysis suggest that oncogenic RAS proteins are involved in the deregulation of the circadian clock in cancer cells (53). Finally, it was recently shown that RASsignaling affects the circadian clock in the suprachiasmatic nucleus of mice acting, at least partially, via ERK and glycogen synthase kinase (GSK), and thereby fine-tunes the circadian period (54).…”

Comparative Analysis of the Effectiveness of Chronotherapy and Traditional Method of Alopecia Areata Treatment

“…In a series of researchers was revealed the presence of circadian rhythms at obstruction of respiratory tracts at pulmonary chronic obstructive diseases [14] and especially asthma [15]. It conditions the necessity of wide introduction of chronotherapy methods in COPD treatment schemes.…”