Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.
Maryam GhashghaeiYilin LiuJames EttlesGiuseppe BombaciNiveditha RamkumarZongmin LiuLeo EscanoSandra Elizabeth SpencerYerin KimJoseph A WaldronKim DoKyle MacPhersonKatie A YuenThilelli TaibiMarty YueAaremish ArsalanZhen JinGlenn EdinAly KarsanGregg B MorinFlorian KuchenbauerFabiana PernaMartin BushellLy Phuong VuPublished in: Nature communications (2024)
Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.
Keyphrases
- acute myeloid leukemia
- allogeneic hematopoietic stem cell transplantation
- poor prognosis
- dendritic cells
- cell cycle arrest
- binding protein
- bone marrow
- oxidative stress
- induced apoptosis
- transcription factor
- gene expression
- single cell
- type diabetes
- regulatory t cells
- cell death
- endoplasmic reticulum stress
- squamous cell carcinoma
- drug delivery
- genome wide
- immune response
- metabolic syndrome
- long non coding rna
- rna seq
- childhood cancer
- network analysis