AU-rich element-binding proteins in colorectal cancer

Abstract

Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a group of RNA-binding proteins called "Adenylate-Uridylate-rich elements binding proteins" (AUBPs) control mRNA stability or translation through their binding to AU-rich elements enriched in the 3'UTRs of inflammation- and cancer-associated mRNA transcripts. AUBPs play a central role in the recruitment of target mRNAs into small cytoplasmic foci called Processing-bodies and stress granules (also known as P-body/SG). Alterations in the expression and activities of AUBPs and P-body/SG assembly have been observed to occur with colorectal cancer (CRC) progression, indicating the significant role AUBP-dependent post-transcriptional regulation plays in controlling gene expression during CRC tumorigenesis. Accordingly, these alterations contribute to the pathological expression of many early-response genes involved in prostaglandin biosynthesis and inflammation, along with key oncogenic pathways. In this review, we summarize the current role of these proteins in CRC development. CRC remains a major cause of cancer mortality worldwide and, therefore, targeting these AUBPs to restore efficient post-transcriptional regulation of gene expression may represent an appealing therapeutic strategy.

Keywords: Adenylate-Uridylate-rich element-binding proteins; Colorectal cancer; Oncogenes; Post-transcriptional regulation; Tumor suppressors.

Figure 1

Network of deregulated adenylate-uridylate-rich elements binding proteins and their targets in colorectal cancer. Adenylate-uridylate-rich elements binding proteins (AUBPs) regulate a large variety of mRNA transcripts involved in cell proliferation, cell death, cancer cell migration, angiogenesis and inflammation at the post-transcriptional level. Some AUBPs interact with each other or compete for the same targets, thus forming a complex network involved in colorectal cancer development. Blue lines indicate positive regulation. Black lines indicate negative regulation. Dashed lines indicate a potential link. microRNAs are represented in red. ABCG2: ATP Binding cassette subfamily G member 2; ALDH1: Aldehyde dehydrogenase 1; ATX: Autotaxin; β-cat: Beta-catenin; BCL2: B-cell lymphoma 2; Bcl2l2: BCL2 like 2; Casp2: Caspase-2; CLDN1: Claudin-1; cIAP2: Cellular inhibitor of apoptosis 2; COX-2: Cyclooxygenase-2; DNMT3a: DNA methyl-transferase 3a; DNMT3b: DNA methyl-transferase 3b; E2F1: E2F transcription factor 1; HIF1a: Hypoxia inducible factor alpha; ICAM1: Intercellular adhesion molecule 1; IL (1β, 6, 23): Interleukins 1β, 6, 23; iNOS: Inducible nitric oxide synthase; LATS: Large tumor suppressor kinase; MACC1: Metastasis associated in colon cancer 1; Mad2L: Mitotic arrest deficient 2 like 1; MDM2: Mouse double minute 2; miR: MicroRNA; NEK2: Nima related kinase 2; PLAGL2: Pleomorphorphic adenoma gene-like 2; PPM1D: Protein phosphatase 1D; SOX9: SRY Box 9; TNFα: Tumor necrosis factor alpha; TP53: Tumor protein 53; VEGF: Vascular endothelium growth factor. XIAP: X-linked inhibitor of apoptosis; Zeb1: Zinc finger E-box binding homeobox 1.

Figure 2

Adenylate-uridylate-rich elements binding proteins are critical regulators of colorectal cancer-associated pathways. Deregulated pathways associated with colorectal cancer development can be regulated by adenylate-uridylate-rich elements binding proteins. Conversely, these pathways can also influence the expression and activity of these proteins. Blue lines indicate positive regulation. Black lines indicate negative regulation. Dashed lines indicate a potential link. AKT: Protein kinase B; ATX: Autotaxin; β-cat: Beta-catenin; COX-2: Cyclooxygenase-2; HDAC: Histone deacetylase; IL6: Interleukin-6; JAK: Janus kinase; LPA: Lysophosphatidic acid; MAPK: Mitogen-activated protein kinase; NFκB: Nuclear factor kappa B; PGs: Prostaglandins; PI3K: Phosphoinositide 3-Kinase; STAT: Signal transducer and activator of transcription; TGFβ: Transforming growth factor beta; YAP: Yes-associated protein.