NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap(4)A) and Down-Regulates Immune Response and Cancer Promotion Genes

Marriott, Andrew S.; Vasieva, Olga; Fang, Yongxiang; Copeland, Nikki A.; McLennan, Alexander G.; Jones, Nigel J.

Cancer. Introduction of Ap 4 A by cold shock into some cell lines has been reported to induce cell cycle arrest and apoptosis [19, 77] . It has also been shown that the level of NUDT2 expression positively correlates with lower survival and increased lymph node metastases in breast carcinoma [78] . This suggests that low Ap 4 A might promote and/or high Ap 4 A might inhibit cancer progression. Given the multifactorial nature of the disease, it is not surprising that IPA 1 classifies 1,108 of the 1,685 DEGs with 2-fold change and P 0.05 as being increased, decreased or affected (usually by mutation association) in cancer. So, to investigate further whether the level of Ap 4 A might correlate with cancer cell proliferation, survival or metastasis, we have further filtered this DEG set to exclude those with FPKM values < 0.3 for both WT and KO samples to focus attention on the more abundant transcripts and avoid any uncertainties about the biological impact of DEGs with low level expression. We then conducted a literature search on the 40 most strongly up-regulated and down-regulated annotated protein-coding genes satisfying these conditions (S7 Table) . Existing experimental evidence suggests that reduced expression of 14 of the top 40 down-regulated genes would lead to a significant anti-cancer effect while reduced expression of only 2 might have a promotional effect. A further 3 could be pro-or anti-cancer depending on cellular context. Of the top 40 up-regulated genes, increased expression of 8 restricts cancer progression in other systems, while only 2 promote it and one could possibly do either (S7 Table) . Thus, increased intracellular Ap 4 A seems to be associated overall with a strong anti-cancer effect. A more detailed appraisal of these genes follows. It is worth noting that the well-characterized FHIT tumor suppressor protein that binds both Ap 3 A and Ap 4 A [8, 79] is not expressed in KBM-7 cells, probably as a result of gene deletion [38] .