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Frequent Loss-of-Function Mutations in MLK4 Suppresses Signaling in the JNK-cJUN-p21/p15 Pathway to Promote Growth of Colon Cancer Cells

ABSTRACT: The goal of the study was to evaluate the influence of mutations in MLK4 on the protein function and the process of tumorigenesis in colorectal cancers. Biochemical data imply that a majority of MLK4 mutations in colon cancer are loss-of-function, including, E314K and Y330H mutations. Two colorectal cell lines, HCT15 and HT115, harboring MLK4 loss-of-function mutations, Y330H and E314K respectively, were used in the study. To evaluate the consequences of loss-of-function MLK4 mutations in those colon cancer cell lines, HCT15 and HT115 cell lines were generated where expression of MLK4-WT (in HCT15 and HT115 cell lines) or MLK4-Y330H (in HCT15 cells) or MLK4-E314K (in HT115 cells) can be induced by tetracycline. The reconstitution of MLK4-WT in colon cancer cells reduced viability, proliferation and ability to form colonies as well as significantly slowed down the tumor growth in mouse xenografts. To investigate the downstream effectors of MLK4 that mediate the above effects, we transcriptionally profiled colon cancer cell lines after MLK4-WT reconstitution. The data indicates that re-expression of functional MLK4 leads to reduction in cell proliferation, likely due to increased expression of cJUN and cdk inhibitors (p15 or p21).

ORGANISM(S): Homo sapiens

PROVIDER: GSE59196 | GEO | 2014/07/09

SECONDARY ACCESSION(S): PRJNA254710

REPOSITORIES: GEO

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Project description:5-Fluorouracil (5-FU) is one of the most effective and widely used chemotherapeutic drugs in the treatment of colon cancer. Yet chemoresistance is a common feature of colon cancer, resulting in poor prognosis and short survival. Dynamic reprogramming of chromatin accessibility allows rapid access of the gene regulatory machinery to open genomic regions facilitating subsequent gene expression via direct transcription factor activation and regulatory element-binding. To better understand the regulatory network underlying 5-FU resistance in colon cancer cells, we explored the systematic alterations of chromatin accessibility and transcript expression by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with transcriptome sequencing, followed by integrative analysis to identify potential regulators and their targets associated with differentially accessible regions (DARs) in 5-FU-resistant HCT15 (HCT15-FR) cells. A total of 3175 differentially expressed mRNAs (DEGs), lncRNAs (DELs) and miRNAs (DEMs) related to 5-FU resistance were identified, including dramatically up-regulated IL33, H19, miR-17-5p, significantly down-regulated AKR1B10, LINC01012, miR-125b-5p, and potential chromatin modifiers such as INO80C, HDAC6 and KDM5A. A competitive endogenous RNAs (ceRNAs) regulatory network was established based on information about interactions among DEGs, DELs and DEMs, suggesting that H19, HOXA11-AS and NEAT1 might function as ceRNAs associate with 5-FU resistance in HCT15 cells. By integrating with transcriptome data, 9868 DARs were identified in HCT15-FR cells compared to control, which were positively (r = 0.58) correlated with their nearest DEGs and DELs. The up-regulated genes related to 4937 increased chromatin-accessible regions were significantly enriched in signaling pathways of MAPK, FOX and WNT, while the 4931 decreased chromatin-accessible regions were considered to be involved in declined biosynthesis of amino acids and nucleotide sugars, signaling pathways of Notch, and HIF-1. Analyses of the DAR sequences revealed that, besides AP-1 family, the TF DNA-binding motifs of FOX and KLF family members were highly enriched in hyper- and hypo-accessible regions, respectively. Moreover, relationships of critical TFs and their potential targets associated with DARs were identified, such as FOXA1, RUNX2, KLF3 and GRHL2. These data provided clear insights and valuable resources for an improved understanding of the non-genetic landscape of 5-FU-resistant colon cancer cells based on chromatin accessibility and transcript levels, which allowed for genome-wide detection of TF-binding sites, potential cis-regulatory elements and therapeutic targets.

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Frequent Loss-of-Function Mutations in MLK4 Suppresses Signaling in the JNK-cJUN-p21/p15 Pathway to Promote Growth of Colon Cancer Cells

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