Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer

Abstract

Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells.

Keywords: colorectal cancer (CRC); competing endogenous RNAs (ceRNA); lncRNA Urothelial Cancer Associated 1 (UCA1); long non-coding RNA (lncRNA).

Figure 1

The function of lncRNAs in the cell. LncRNAs exert different functions in the nucleus, ranging from genomic DNA organization in speckle bodies, histone, and DNA methylation and direct transcriptional regulation (Section 2.1). Through their interaction with mRNA and function in miRNA regulation, they affect protein translation (Section 2.2). In addition, they interact with proteins, affecting stability, activity, and/or complex recruitment (Section 2.3).

Figure 2

The regulation by Urothelial Cancer Associated 1 (UCA1)-associated miRNAs. All 29 miRNAs published to interact with UCA1 (Table 4) were submitted to the miRNA network analysis tool ONCO.IO and the downstream-regulated genes are visualized (https://onco.io/main.php). In the overall UCA1/miRNA image, genes were sorted based on the number of miRNAs bound per gene. The genes associated with over 5 miRNAs (circled) include VEGF, KRAS, BCL2, EZH2, receptor ESR1; transcription factors: STAT3, RUNX, SOX4, MYC, TP53; lncRNA MALAT; and the kinases IGF1R and CDK4. Genes that were associated with the indicated signaling pathways are also represented in individual images.

Figure 3

The UCA1-mediated regulation in colorectal cancer cells. (A) Schematically representation of UCA1 regulating key actors for cell cycle progression during G1 and S-phase in diverse cancer cell types. (B) All 29 miRNAs published to interact with UCA1 in diverse cancer cell types (Table 4) were submitted to the miRNA network analysis tool ONCO.IO and their interaction with chemoresistance-related genes were visualized (Receptors: TGFBR2, NOTCH1, FGFR1; Transcriptional regulating factors: HMGA2 and HIF1A; cell cycle kinase ATM, CDKN1 (p27); FLAG1, RAB22A, BAK1, BAX, ABCB1 (MDR1), ABCC1 (MRP1), MCL1, and BCL2).