ArticleCell death and differentiation2022
Loss of circadian gene Timeless induces EMT and tumor progression in colorectal cancer via Zeb1-dependent mechanism.
Article in Cell death and differentiation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 64 citations in OpenAlex.
- Zinc finger proteins (ZFPs) in health and disease.Molecular biomedicine · 2026Review
- The circadian clock component PER2 deficiency aggravates airway epithelial remodeling through Wnt/β-catenin signaling pathway.Respiratory research · 2026Article
- Temporal dynamics in cancer immunotherapy: the interplay between circadian rhythms, tumor microenvironment, and immune checkpoint blockade.Journal of the National Cancer Center · 2026Review
- Circadian Clock Genes in Colorectal Cancer: From Molecular Mechanisms to Chronotherapeutic Applications.Biomedicines · 2026Review
- TIMELESS Promotes LUAD Growth via Suppressing Transferrin-Mediated Ferroptosis and Reprograms the Tumor Microenvironment against Anti-PD-1 Immunotherapy.Cancer communications (London, England) · 2026Article
- rs10204525 binding to miR-4717-3p modulates PD-1 expression and predicts the development of immune-related adverse events in patients with advanced cancer treated with anti-PD-1/PD-L1 therapy.Journal for immunotherapy of cancer · 2025Article
- PLIN2 promotes colorectal cancer progression through CD36-mediated epithelial-mesenchymal transition.Cell death & disease · 2025Article
- miR-200a-3p promotes the malignancy of endometrial carcinoma through negative regulation of epithelial-mesenchymal transition.Discover oncology · 2024Article
- Restoring BARX2 in OSCC reverses partial EMT and suppresses metastasis through miR-186-5p/miR-378a-3p-dependent SERPINE2 inhibition.Oncogene · 2024Article
- rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC.Molecular cancer · 2024Article
- Article
- The Circadian Clock as a Potential Biomarker and Therapeutic Target in Gastrointestinal Cancers.Current pharmaceutical design · 2024Review
- SP3-induced Timeless transcription contributes to cell growth of lung adenocarcinoma cells.PloS one · 2024Article
- Transcription factor ZEB1 coordinating with NuRD complex to promote oncogenesis through glycolysis in colorectal cancer.Frontiers in pharmacology · 2024Article
- An integrative evaluation of circadian gene TIMELESS as a pan-cancer immunological and predictive biomarker.European journal of medical research · 2023Article
- Six-hour time-restricted feeding inhibits lung cancer progression and reshapes circadian metabolism.BMC medicine · 2023Article
- Clostridium butyricum inhibits epithelial-mesenchymal transition of intestinal carcinogenesis through downregulating METTL3.Cancer science · 2023Article
- Gene Expression Analysis Links Autocrine Vasoactive Intestinal Peptide and ZEB1 in Gastrointestinal Cancers.Cancers · 2023Article
- Relationship between Epithelial-to-Mesenchymal Transition and Tumor-Associated Macrophages in Colorectal Liver Metastases.International journal of molecular sciences · 2022Review
- Circadian clock as a possible control point in colorectal cancer progression (Review).International journal of oncology · 2022Review
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The circadian gene Timeless (TIM) provides a molecular bridge between circadian and cell cycle/DNA replication regulatory systems and has been recently involved in human cancer development and progression. However, its functional role in colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide, has not been fully clarified yet. Here, the analysis of two independent CRC patient cohorts (total 1159 samples) reveals that loss of TIM expression is an unfavorable prognostic factor significantly correlated with advanced tumor stage, metastatic spreading, and microsatellite stability status. Genome-wide expression profiling, in vitro and in vivo experiments, revealed that TIM knockdown induces the activation of the epithelial-to-mesenchymal transition (EMT) program. Accordingly, the analysis of a large set of human samples showed that TIM expression inversely correlated with a previously established gene signature of canonical EMT markers (EMT score), and its ectopic silencing promotes migration, invasion, and acquisition of stem-like phenotype in CRC cells. Mechanistically, we found that loss of TIM expression unleashes ZEB1 expression that in turn drives the EMT program and enhances the aggressive behavior of CRC cells. Besides, the deranged TIM-ZEB1 axis sets off the accumulation of DNA damage and delays DNA damage recovery. Furthermore, we show that the aggressive and genetically unstable 'CMS4 colorectal cancer molecular subtype' is characterized by a lower expression of TIM and that patients with the combination of low-TIM/high-ZEB1 expression have a poorer outcome. In conclusion, our results as a whole suggest the engagement of an unedited TIM-ZEB1 axis in key pathological processes driving malignant phenotype acquisition in colorectal carcinogenesis. Thus, TIM-ZEB1 expression profiling could provide a robust prognostic biomarker in CRC patients, supporting targeted therapeutic strategies with better treatment selection and patients' outcomes.
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