The transcription factor ATF4 regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses, and it is overexpressed in human solid tumours, suggesting that it has an important function in tumour progression. Here, we report that inhibition of ATF4 expression blocked proliferation and survival of transformed cells, despite an initial activation of cytoprotective macroautophagy. Knockdown of ATF4 significantly reduced the levels of asparagine synthetase (ASNS) and overexpression of ASNS or supplementation of asparagine in trans, reversed the proliferation block and increased survival in ATF4 knockdown cells. Both amino acid and glucose deprivation, stresses found in solid tumours, activated the upstream eukaryotic initiation factor 2a (eIF2a) kinase GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport. GCN2 activation/overexpression and increased phospho-eIF2a were observed in human and mouse tumours compared with normal tissues and abrogation of ATF4 or GCN2 expression significantly inhibited tumour growth in vivo. We conclude that the GCN2-eIF2a-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches.
BackgroundDynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m6A-methylation in hepatocellular carcinoma (HCC).ResultsUsing liquid chromatography-tandem mass spectrometry and m6A-immunoprecipitation in combination with high-throughput sequencing, we determined the m6A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m6A modification in tandem with an increase of mRNA expression, owing to YTH domain family 2 (YTHDF2) reduction. The latter predicted poor classification and prognosis of HCC patients, and highly correlated with HCC m6A landscape. YTHDF2 silenced in human HCC cells or ablated in mouse hepatocytes provoked inflammation, vascular reconstruction and metastatic progression. Mechanistically, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy and disruption of vascular normalization. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer.ConclusionOur results have characterized the m6A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular ‘rheostat’ in epitranscriptome and cancer progression.
Entry-level kindergartners in classrooms from five middle class school districts were given a test of letter identification and children who scored at or below the 30th percentile on the test were classified as ''at risk'' for early reading difficulties. Half of these children were randomly assigned to a project-based intervention condition where they received supplementary intervention in small groups until the end of their kindergarten year. The other half received whatever remedial services were available at their home schools and literacy skills development in both groups was tracked throughout kindergarten. All available at-risk children were again assessed at the beginning of first grade and dichotomized into a ''continued-risk'' group and a ''no-longer-at-risk'' group using a composite measure of basic word level skills. Normal reader controls were also identified using the same measure. Children in the continued-risk group received either project-based intervention (one-to-one tutoring 30 min daily) or school-based intervention throughout first grade. Intervention for project treatment children was discontinued at the end of first grade and literacy development in all groups was tracked until the end of third grade. The present study focused on literacy development in children who received only project-based kindergarten intervention or both (project-based) kindergarten and first grade intervention, relative to the normal reader controls. Of special interest was the question of whether measures of response to intervention would more effectively distinguish between continued-risk and no-longer-at-risk children than would kindergarten screening measures, measures of intelligence, or measures of reading-related cognitive abilities. Results indicated that the RTI
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