Transcriptome analysis implicates MYC as a driver of early onset colorectal cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA802883 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17866817_1.fastq.gz | Fastqsanger.gz | |||
| SRR17866817_2.fastq.gz | Fastqsanger.gz | |||
| SRR17866818_1.fastq.gz | Fastqsanger.gz | |||
| SRR17866818_2.fastq.gz | Fastqsanger.gz | |||
| SRR17866819_1.fastq.gz | Fastqsanger.gz |
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Project description:Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has been steadily increasing over the past several decades. When compared to later onset colorectal cancers (LOCRCs) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analysis of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis. Amongst differentially expressed genes, we found increased expression of the c-MYC (MYC) proto-oncogene and its downstream targets in tumor samples. We identify tumors with high and low differential MYC expression, and patients with high-MYC tumors were older and overweight or obese. We also detect elevated expression of the PVT1 long-non-coding RNA (lncRNA) in most tumors and find gains in copy number for both MYC and PVT1 gene loci in 35% of tumors evaluated. Our transcriptome analysis indicates that EOCRC can be sub-classified into groups based on differential MYC expression and suggests that MYC is a critical driver of most CRCs that develop in younger patients.
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Project description:Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing over the last decades worldwide with causes unexplained. A unique molecular feature of EOCRC is that these cases harbor a greater incidence of Nodal Modulator 1 (NOMO1) somatic deletions compared with late-onset CRC. Yet the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. Here we show that 50% of heterozygous NOMO1 deleted–EOCRCs presented pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study its role in EOCRC, CRISPR/cas9 technology was used to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. Loss of NOMO1 in these cell lines did not perturb Nodal pathway signaling. Results from expression microarray, RNA sequencing and protein expression analysis by LC-IMS/MS revealed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway such as epithelial-mesenchymal transition. Importantly, NOMO1 inactivation increased the migration capacity of CRC cells. Additionally, a gut-specific conditional KO mouse model of NOMO1 revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could not be a driver of early-onset colorectal carcinogenesis, but its loss promotes an increased migration capacity of CRC cells. Further study is warranted to explore other signaling pathways deregulated by the loss of NOMO1 that may play a relevant role in the pathogenesis of the disease.
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Project description:Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARFBP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells. MIZ1 and MYC ChIPseq experiments in HUWE1 inhibitor-treated Ls174T cells as well as RNAseq experiments in HUWE1- or MIZ1-depleted Ls174T cells after HUWE1 inhibitor treatment. Sequencing was performed on an Illumina Genome Analyzer IIx.
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Project description:Early-Onset Colorectal Carcinoma (EOCRC) is a growing concern as reports indicate a worldwide increase in the incidence of CRC among young adults (<50 years old). In an effort to understand the different mode of pathogenesis in young-onset CRC, we performed a pilot study wherein we looked at colorectal tumors from both young (< 50 years old) and old patients (>55 years old) and screened them to eliminate tumors positive for Microsatellite Instability (MSI) and showing activation of the Wnt pathway, known canonical factors in CRC pathogenesis. RNA isolated from 3 EOCRC and 2 Late-Onset (LOCRC) tumors and paired normal tissues without MSI, nuclear β-catenin and APC mutations were sent for small RNA seq to identify miRNA alterations between the two subsets. Comparative analysis revealed differential expression of 23 miRNAs specific to EOCRC and 11 miRNAs specific to LOCRC.
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Project description:Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARFBP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.
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