Profound alterations of cancer transcriptomes by the RNase L inhibitor ABCE1 through the modulation of UU/UA-dinucleotide rich transcript abundance.

Tumorigenesis is commonly driven by genetic mutations and disruptions in cellular signalling pathways. Here we show that the oncogenic overexpression of the RNase L inhibitor ABCE1, a component of interferon signalling, leads to distinct and extensive deviations in cancer transcriptomes. RNase L is a cellular endonuclease that cleaves RNA molecules at specific UU and UA dinucleotide sites. Typically, it is activated by viral infections and interferon signalling leading to targeting and destruction of UU/UA-rich viral and cellular mRNA. RNase L has also homoeostatic and tumour suppressive roles. Relying on patient transcriptomic data, we show that ABCE1 is extensively overexpressed in colorectal cancer (CRC) and to a lesser extent in lung cancer. This upregulation was strongly associated with the co-upregulation of almost all UU/UA rich transcripts and downregulation of those that are UU/UA-poor. Many of upregulated mRNAs code for proteins involved in cell cycle regulation and mitosis. Accordingly, the knockdown of ABCE1 in the CRC cell line HT29 led to reduced proliferation. Surprisingly, the very high ABCE1 levels were associated with improved patient survival in CRC. This observation might be related to an anti-ABCE1-specific immune response due to the induction of tumour-reactive cytotoxic T lymphocytes by ABCE1 as previously reported. In lung cancer ABCE1 overexpression is milder and is associated with poor survival. We report a measurable, specific, and extensive modulation of cancer transcriptomes by the oncogenic overexpression of a component of interferon signalling with unexpected outcomes on patient survival.