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Genome-wide expression profiling of CRC cells (SW620) upon TIMELESS loss expression and/or ZEB1 down regulation

ABSTRACT: Colorectal cancer (CRC) is the third most common cancer worldwide. Recent studies pinpointed TIMELESS (TIM) to be crucially involved in replication protection/genomic stability, DNA damage response (DDR) and coordination of mitotic kinase activation with DNA replication termination. Here we present the first direct evidence of a TIM-ZEB1 axis which control key pathological processes in CRC. We found that loss of TIM expression unleashes ZEB1 which triggers epithelial-to-mesenchymal transition program, cell migration/invasion increase and acquirement of stem-like phenotype of CRC cells. Besides, deranged TIM-ZEB1 axis sets off accumulation of DNA damage and delays DNA damage recovery. It is worth noting that the aggressive and genetically unstable ‘CMS4 - colorectal cancer molecular subtype’ matched with low-TIM expressing CRCs and that patients with low-TIM and high-ZEB1 expression have an adverse outcome. Our results support a critical role for TIM-ZEB1 axis derangement and modulation in determining aggressive disease and poor prognosis in CRC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169576 | GEO | 2022/01/17

REPOSITORIES: GEO

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Project description:Background: Colorectal cancer (CRC) is an aggressive primary intestinal malignancy with the third-highest incidence and second-highest mortality among all cancer types worldwide. Transcription factors (TFs) regulate cell development and differentiation owing to their ability to recognize specific DNA sequences upstream of genes. Numerous studies have demonstrated a strong correlation between TFs, the etiology of tumors, and therapeutic approaches. Here, we aimed to explore prognosis-related TFs and comprehend their carcinogenic mechanisms, thereby offering novel insights into the diagnosis and management of CRC. Materials and methods: Differentially expressed TFs between CRC and normal tissues were identified leveraging The Cancer Genome Atlas database, Weighted correlation network analysis and Cox regression analysis were performed to identify prognosis-related TFs. The cellular functions of hub TF zinc finger E-box binding homeobox 1 (ZEB1) were determined using by 5-ethynyl-2'-deoxyuridine and cell invasion assays in CRC cells. RNA-sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment, and gene set enrichment analyses were used to identify the cellular processes in which ZEB1 participates. Immunoaffinity purification, silver staining mass spectrometry, and a chromatin immunoprecipitation assay were conducted to search for proteins that might interact with ZEB1 and the target genes they jointly regulate. Results: Thirteen central TFs related to prognosis were identified through bioinformatics analysis techniques. Among these TFs, ZEB1 emerged as the TF most closely associated with CRC, as determined through a combination of regulatory network diagrams, survival curves, and phenotype analyses. ZEB1 promotes CRC cell growth by recruiting the NuRD(MTA1) complex, and the ZEB1/NuRD(MTA1) complex transcriptionally represses glycolysis-associated tumor suppressor genes. Conclusion: Our study not only identified a hub biomarker related to CRC prognosis but also revealed the specific molecular mechanisms through which ZEB1 affects cancer progression. These insights provide crucial evidence for the diagnosis of CRC and potential treatment opportunities.

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Genome-wide expression profiling of CRC cells (SW620) upon TIMELESS loss expression and/or ZEB1 down regulation

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