Grade IV astrocytoma or glioblastoma multiforme (GBM) is one of the most aggressive and lethal tumors affecting humans. ADAR2-mediated A-to-I RNA editing, an essential post-transcriptional modification event in brain, is impaired in GBMs and astrocytoma cell lines. However, the role of ADAR2 editing in astrocytomas remains to be defined. Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma. We demonstrate that ADAR2 deaminase activity is essential to inhibit tumor growth. Indeed, we identify the phosphatase CDC14B, which acts upstream of the Skp2/p21/p27 pathway, as a novel and critical ADAR2 target gene involved in glioblastoma growth. Specifically, ADAR2-mediated editing on CDC14B pre-mRNA increases its expression with a consequent reduction of the Skp2 target protein, as shown both in vitro and in vivo. We found that, compared to normal brain, both CDC14B editing and expression are progressively impaired in astrocytomas from grade I to IV, being very low in GBMs. These findings (1) demonstrate that post-transcriptional A-to-I RNA editing might be crucial for glioblastoma pathogenesis, (2) identify ADAR2-editing enzyme as a novel candidate tumor suppressor gene and (3) provide proof of principle that ADAR2 or its substrates may represent a suitable target(s) for possible novel, more effective and less toxic approaches to the treatment of GBMs.

Slowing down mRNA translation in either the cytoplasm or the mitochondria are conserved longevity mechanisms. Here, we found a non-interventional natural correlation of mitochondrial and cytoplasmic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance between these two compartments. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed overall cytoplasmic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced the translational efficiency (TE) of mRNAs required in growth pathways while increasing the TE of stress response mRNAs. The coordinated repression of cytoplasmic translation is dependent on atf-5/Atf4 and is conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with the antibiotic doxycycline. Lastly, extending this in vivo, doxycycline repressed cytoplasmic translation and RP expression in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/Atf4-dependent cascade leading to coordinated repression of cytoplasmic translation, which could be targeted to promote longevity. Keywords longevity / ribosomes / mitochondrial translation / cytoplasmic translation / translational balance Highlights • Mitochondrial and cytoplasmic RP levels balance in a natural stoichiometric ratio • Blocking mitochondrial ribosomes in worms and mice reduces cytoplasmic translation • This translational balance is ATF4/atf-5 dependent and conserved in human cells • Translational efficiency of RP transcripts changes in response to ratio requirement

Deregulated global mRNA translation is an emerging feature of cancer cells. Oncogenic transformation in colorectal cancer (CRC) is driven by mutations in APC, KRAS, SMAD4, and TP53, known as the adenoma-carcinoma sequence (ACS). Here we introduce each of these driver mutations into intestinal organoids to show that they are modulators of global translational capacity in intestinal epithelial cells. Increased global translation resulting from loss of Apc expression was potentiated by the presence of oncogenic KrasG12D. Knockdown of Smad4 further enhanced global translation efficiency and was associated with a lower 4E-BP1-to-eIF4E ratio. Quadruple mutant cells with additional P53 loss displayed the highest global translational capacity, paralleled by high proliferation and growth rates, indicating that the proteome is heavily geared toward cell division. Transcriptional reprogramming facilitating global translation included elevated ribogenesis and activation of mTORC1 signaling. Accordingly, interfering with the mTORC1/4E-BP/eIF4E axis inhibited the growth potential endowed by accumulation of multiple drivers. In conclusion, the ACS is characterized by a strongly altered global translational landscape in epithelial cells, exposing a therapeutic potential for direct targeting of the translational apparatus.