ALKBH8-Mediated Codon-Specific Translation Promotes Colorectal Tumorigenesis
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ABSTRACT:
PROVIDER: PRJNA1166187 | ENA |
REPOSITORIES: ENA
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Project description:Reprogramming gene expression at the translational level drives intestinal tumorigenesis. Codon decoding during translation elongation relies on tRNA modifications, while their pathological relevance in colorectal cancer remains to be elucidated. Here, we show that AlkB homolog 8 (ALKBH8), a uridine 34 (U34) tRNA methyltransferase, is a direct target of Wnt/β-catenin and is upregulated in colorectal cancer. Genetic ablation of ALKBH8 inhibits the development of intestinal tumors in Apcmin/+, AOM/DSS, and xenograft models. Loss of ALKBH8 induces ribosome pausing at adenine-ending codons, impairing the translation elongation of mRNAs enriched with these codons. Specifically, ALKBH8 regulates the translation of KRAS proto-oncogene in a codon-dependent manner. Rescue experiments demonstrate that the methyltransferase activity of ALKBH8 is required for its translation-promoting function. Together, our findings reveal ALKBH8-dependent mRNA translation as a critical mediator of intestinal tumorigenesis, underscoring its potential as a promising target for colorectal cancer therapy.
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Project description:Alternate translation initiation expands protein diversity which is adopted by cancers for progression. However, the majority of these alternative initiation events in cancers remain largely undefined. In this study, we demonstrate that the human hydroxyacyl-CoA dehydrogenase (HADH) gene, catalyzing the third step of the mitochondrial β-oxidation cascade, has two alternative translation start codons. The translation from the downstream start codon produces a short isoform (HADH-S) primarily localized in the nucleus. HADH-S is downregulated in colorectal cancer. Overexpression of HADH-S inhibits colorectal tumorigenesis in vitro and in vivo. Mechanistically, HADH-S antagonizes protein arginine methyltransferase 5 (PRMT5)-mediated histone arginine methylation, thereby facilitating gene transcription. Notably, HADH promotes the transcription of the Wnt suppressor AXIN2. These findings collectively identify a novel nuclear isoform of HADH that exerts inhibitory effects on colorectal tumorigenesis.
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Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.
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Project description:Ribosome profiling data reports on the distribution of translating ribosomes, at steady-state, with codon-level resolution. We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast. We show that neither elongation rate nor translational efficiency is improved by experimental manipulation of the abundance or body sequence of the rare AGG tRNA. Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start. This suggests that correlation between codon bias and efficiency arises as selection for codons to utilize translation machinery efficiently in highly translated genes. We also show a correlation between efficiency and RNA structure calculated both computationally and from recent structure probing data, as well as the Kozak initiation motif, which may comprise a mechanism to regulate initiation. We test whether tRNA abundance affects elongation or translation efficiency by changing the tRNA levels through deletion or over expression and measuring the ribosomal dwell time at each codon using a robust statistical method that accounts for flow conservation.
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Project description:Gut microbiota dysbiosis and immune dysregulation are closely linked to colorectal cancer development. Identifying mechanistic connections among specific microbial species, metabolites, and immune responses may reveal novel insights into its pathogenesis. Here, employing metagenomic, metabolomic, and single-cell transcriptomic analyses across clinical cohorts, we identify Fusobacterium periodonticum as significantly enriched in colorectal cancer patients and strongly correlated with elevated decanoic acid levels, and further reveal tissue-specific neutrophil enrichment in colorectal cancer. Cellular experiments demonstrate that decanoic acid induces neutrophil late apoptosis/necrosis and enhances chemotaxis through a pertussis toxin-sensitive G-protein-dependent mechanism, while upregulating genes associated with leukocyte migration and tumorigenesis. Mouse models further confirm that F. periodonticum colonization increases dysplasia and decanoic acid levels, and that decanoic acid intervention promotes tumor progression through neutrophil infiltration and immune modulation. Our study reveals an important role of F. periodonticum in colorectal tumorigenesis via decanoic acid-medicated neutrophil chemotaxis, providing new insights into colorectal cancer pathogenesis
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