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.

Several other prominent DEGs are known to affect growth and apoptosis in other systems. The Wilms' tumor transcriptional regulator WT1 can exhibit both oncogenic and tumor suppressor activities depending on its association with specific co-regulators [104, 105] . For example, the co-repressor BASP1 interacts with WT1 in a complex with PHB and BRG1 to favor growth arrest and the induction of apoptosis over proliferation [106] . All these genes are well expressed in KBM-7 cells, with BASP1 exhibiting 35-fold up-regulation in NuKO cells. Up-regulation of IFI44L is associated with melanoma and prostate cancer [107, 108] while overexpression of NKX2-2 is associated with Ewing's sarcoma and fibromatosis [109] . They are down 224-and 125-fold respectively in NuKO cells. The homeobox transcription factor NKX3-1 is a prostate tumor suppressor [110] and its expression is increased 13-fold in NuKO cells. Overexpression of the coiled coil domain protein CCDC68 decreased proliferation and tumorigenicity of pancreatic ductal adenocarcinoma cells while allelic loss was found in about half the tumors examined [111] . It has also been identified as a possible tumor suppressor in colorectal cancer [112] and is up-regulated 11-fold in NuKO cells. Even genes with a more modest change in expression could have a profound anti-cancer effect; for example, Interferon Regulatory Factor 4 (IRF4), an important NF-κB-activated regulator of immune system development and the innate immune response [113] , also plays an essential role in many lymphoid malignancies, and knockdown of its expression by only 50% is lethal to multiple myeloma cells [114, 115] . It is down-regulated 7-fold in NuKO cells.