The involvement od DIS3L2 in nonsense-mediated mRNA decay and its functional networks in colorectal cancer

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DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway

Publication . García-Moreno, Juan F.; Lacerda, Rafaela; da Costa, Paulo J.; Pereira, Marcelo; Gama-Carvalho, Margarida; Matos, Paulo; Romão, Luísa

DIS3L2 degrades different types of RNAs in an exosome-independent manner including mRNAs and several types of non-coding RNAs. DIS3L2-mediated degradation is preceded by the addition of nontemplated uridines at the 3’end of its targets by the terminal uridylyl transferases 4 and 7. Most of the literature that concerns DIS3L2 characterizes its involvement in several RNA degradation pathways, however, there is some evidence that its dysregulated activity may contribute to cancer development. In the present study, we characterize the role of DIS3L2 in human colorectal cancer (CRC). Using the public RNA datasets from The Cancer Genome Atlas (TCGA), we found higher DIS3L2 mRNA levels in CRC tissues versus normal colonic samples as well as worse prognosis in patients with high DIS3L2 expression. In addition, our RNA deep-sequencing data revealed that knockdown (KD) of DIS3L2 induces a strong transcriptomic disturbance in SW480 CRC cells. Moreover, gene ontology (GO) analysis of significant upregulated transcripts displays enrichment in mRNAs encoding proteins involved in cell cycle regulation and cancer-related pathways, which guided us to evaluate which specific hallmarks of cancer are differentially regulated by DIS3L2. To do so, we employed four CRC cell lines (HCT116, SW480, Caco-2 and HT-29) differing in their mutational background and oncogenicity. We demonstrate that lack depletion of DIS3L2 results in reduced cell viability of highly oncogenic SW480 and HCT116 CRC cells, but had little or no impact in the more differentiated Caco-2 and HT-29 cells. Remarkably, the mTOR signaling pathway, crucial for cell survival and growth, is downregulated after DIS3L2 KD, whereas AZGP1, an mTOR pathway inhibitor, is upregulated. Furthermore, our results indicate that depletion of DIS3L2 disturbs metastasis-associated properties, such as cell migration and invasion, only in highly oncogenic CRC cells. Our work reveals for the first time a role for DIS3L2 in sustaining CRC cell proliferation and provides evidence that this ribonuclease is required to support the viability and invasive behavior of dedifferentiated CRC cells.

2023-06-20Journal article

Open access

DIS3L2: Unveiling a New Player in Tumorigenesis, with a Key Role in Colorectal Cancer

Publication . García-Moreno, Juan F.; Matos, Paulo; Romão, Luísa

DIS3L2 is a 3’-5’ exoribonuclease that recognizes and degrades uridylated transcripts in an exosome-independent manner and participates in several RNA degradation pathways, such as the nonsense-mediated mRNA decay, or the surveillance of aberrant structured non-coding RNAs. Although some studies have linked DIS3L2 to tumorigenesis and cancer-related processes, its exact role in the development and progression of cancer has remained unclear since the discovery of DIS3L2's ribonuclease activity a decade ago. While some authors have reported evidence of a tumor suppressor role for this exoribonuclease, other studies have shown DIS3L2 as a driver of tumorigenesis. Although differences in tissue type and methodologic approaches may somewhat account for the opposing findings, a recent study from our group further supports a pro-tumorigenic role for DIS3L2, this time in promoting colorectal cancer (CRC) progression. Indeed, proper DIS3L2 expression was proven essential to maintain key tumorigenic properties in CRC cells, including cell proliferation and invasion. Here, we summarize the current state of knowledge regarding the impact of DIS3L2 in cancer, namely in colorectal cancer. The collected data unveils DIS3L2 as a novel putative therapeutic target in cancer that warrants further investigation.

2023Periodical

Open access