FTO degrader inhibits acute myeloid leukemia by impairing ribosome biogenesis and translation
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ABSTRACT:
PROVIDER: PRJNA1190481 | ENA |
REPOSITORIES: ENA
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Project description:The fat mass and obesity-associated protein (FTO), an RNA m6A eraser, has been identified as a critical oncogenic factor in acute myeloid leukemia (AML). We presented the development of an FTO degrader(FP54) that selectively degrades FTO in AML cells, demonstrating superior efficacy both in vitro and in vivo. Mechanistically, FTO degradation increases m6A modifications on ribosome biogenesis related mRNAs and thus promotes YTHDF2-mediated degradation. This process impairs ribosome biogenesis and translation process, ultimately inhibiting AML progression.
2025-07-08 | GSE282823 | GEO
Project description:Ribosome profiling (RP) results of MDA-MB-231 cells; two scrambled shRNA control (SCR) replicates and two FTO knockdown (shFTO) replicates.
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Project description:The m6A RNA demethylase Fat mass and obesity-associated protein (FTO) is aberrantly upregulated in numerous cancers and promotes tumor development and therapeutic resistance. Here, using public datasets and screening, we show that FTO is ubiquitinated at lysine 162 by its E3 ligase DTX2, followed by recognition by UFD1, leading to degradation in the proteasomes. Furthermore, we identified vitamin E succinate (VES) as a natural first-in-class degrader for FTO by binding to FTO and DTX2, thus enhancing FTO-DTX2 interaction, leading to increased FTO ubiquitination and degradation and enhanced anti-tumor immunity and response to immunotherapy. Genetic or pharmacological FTO knockdown by VES increased m6A methylation in the LIF gene and thus decreased LIF mRNA decay, and thus sensitized tumor cells to T cell-mediated cytotoxicity. Taken together, our findings elucidated the underlying molecular mechanism for FTO protein degradation and the first natural FTO degrader that reprograms the anti-tumor immunity.
2024-11-25 | GSE250332 | GEO
Project description:Post-transcriptional regulation of Ribosome Biogenesis
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Project description:The budding yeast E3 SUMO ligase Mms21, a component of the Smc5-6 complex, regulates sister chromatid cohesion, DNA replication, and DNA repair. We identify a role for Mms21 in ribosome biogenesis. The mms21RINGD mutant exhibits reduced rRNA production, nuclear accumulation of 60S and 40S ribosomal proteins, and elevated Gcn4 translation. Genes involved in ribosome biogenesis and translation are down-regulated in the mms21RINGD mutant. Examining gene expression profile of mms21RINGD mutant compared to wild-type by RNA Seq using Ilumina sequencing
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Project description:FTO controls reversible m6Am RNA methylation during snRNA biogenesis
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Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
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Project description:Small nuclear RNAs (snRNAs) are core spliceosome components and mediate pre-mRNA splicing. Here we show that snRNAs contain a regulated and reversible nucleotide modification causing them to exist as two different methyl isoforms, m 1 and m 2 , reflecting the methylation state of the adenosine adjacent to the snRNA cap. We find that snRNA biogenesis involves the formation of an initial m 1 isoform with a single-methylated adenosine (2′-O-methyladenosine, Am), which is then converted to a dimethylated m 2 isoform (N 6 ,2′-O-dimethyladenosine, m 6 Am). The relative m 1 and m 2 isoform levels are determined by the RNA demethylase FTO, which selectively demethylates the m 2 isoform. We show FTO is inhibited by the oncometabolite d-2-hydroxyglutarate, resulting in increased m 2 -snRNA levels. Furthermore, cells that exhibit high m 2 -snRNA levels show altered patterns of alternative splicing. Together, these data reveal that FTO controls a previously unknown central step of snRNA processing involving reversible methylation, and suggest that epitranscriptomic information in snRNA may influence mRNA splicing.
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Project description:Catalytic Activity of ADAR1 Governs Ribosome Biogenesis
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Project description:In all domains of life, the rate of protein synthesis is directly linked to the rates of cell growth and proliferation. Consequently, highly proliferative cancer cells are especially sensitive to perturbations in ribosome biogenesis. While ribosome synthesis and cancer have a well-established relationship, only recently has ribosome biogenesis drawn interest as a cancer therapeutic target. Here, we have exploited the relationship between ribosome biogenesis and cancer cell proliferation by using a potent ribosome biogenesis inhibitor: RBI2 (Ribosome Biogenesis Inhibitor 2) to perturb cancer cell growth and viability. We demonstrate that RBI2 significantly decreases cell viability in malignant melanoma cells and breast cancer cell lines. Treatment with RBI2 dramatically and rapidly decreases ribosomal RNA (rRNA) synthesis, without affecting the occupancy of RNA polymerase I (Pol I) on the ribosomal DNA template. Next-generation RNA sequencing (RNA-seq) reveals that RBI2 and previously described ribosome biogenesis inhibitor CX-5461 induce distinct changes in the transcriptome. Investigation of the content of the pre-rRNAs through RT-qPCR reveals an increase in polyadenylation of cellular rRNA after treatment with RBI2, a known pathway by which rRNA degradation occurs. Northern blotting revealed that RBI2 does not appear to impair or alter rRNA processing. Collectively, these data suggest that RBI2 inhibits rRNA synthesis distinctly from other previously described ribosome biogenesis inhibitors, potentially through a novel pathway that upregulates turnover of premature rRNAs.
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