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1.
Nat Commun ; 15(1): 2340, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38491013

ABSTRACT

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.


Subject(s)
Leukemia, Myeloid, Acute , Proteomics , Transcription Factors , Humans , Carcinogenesis/genetics , Cell Differentiation , Leukemia, Myeloid, Acute/genetics , Receptors, CCR4 , Transcription Factors/genetics , Transcription Factors/metabolism
2.
Blood Adv ; 7(15): 3846-3861, 2023 08 08.
Article in English | MEDLINE | ID: mdl-36322827

ABSTRACT

Regulation of gene expression at the RNA level is an important regulatory mechanism in cancer. However, posttranscriptional molecular pathways underlying tumorigenesis remain largely unexplored. In this study, we uncovered a functional axis consisting of microRNA (miR)-148a-3p, RNA helicase DDX6, and its downstream target thioredoxin-interacting protein (TXNIP) in acute myeloid leukemia (AML). Using a DROSHA-knockout cell system to evaluate miR-mediated gene expression control, we comprehensively profiled putative transcripts regulated by miR-148a-3p and identified DDX6 as a direct target of miR-148a-3p in AML cells. DDX6 depletion induced cell cycle arrest, apoptosis, and differentiation, although delaying leukemia development in vivo. Genome-wide assessment of DDX6-binding transcripts and gene expression profiling of DDX6-depleted cells revealed TXNIP, a tumor suppressor, as the functional downstream target of DDX6. Overall, our study identified DDX6 as a posttranscriptional regulator that is required for AML survival. We proposed the regulatory link between miR-148a-3p and DDX6 as a potential therapeutic target in leukemia.


Subject(s)
Leukemia, Myeloid, Acute , MicroRNAs , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Genes, Tumor Suppressor , Leukemia, Myeloid, Acute/genetics , Cell Differentiation/physiology , Proto-Oncogene Proteins/genetics , DEAD-box RNA Helicases/genetics
3.
ACS Infect Dis ; 5(3): 443-453, 2019 03 08.
Article in English | MEDLINE | ID: mdl-30565465

ABSTRACT

Antimicrobial peptides have been the focus of considerable research; however, issues associated with toxicity and aggregation have the potential to limit clinical applications. Here, a derivative of a truncated version of aurein 2.2 (aurein 2.2Δ3), namely peptide 73, was investigated, along with its d-amino acid counterpart (D-73) and a retro-inverso version (RI-73). A version that incorporated a cysteine residue to the C-terminus (73c) was also generated, as this form is required to covalently attach antimicrobial peptides to polymers (e.g., polyethylene glycol (PEG) or hyperbranched polyglycerol (HPG)). The antimicrobial activity of the 73-derived peptides was enhanced 2- to 8-fold, and all the derivatives eradicated preformed Staphylococcus aureus biofilms. Formulation of the peptides with compatible polyethylene glycol (PEG)-modified phospholipid micelles alleviated toxicity toward human cells and reduced aggregation. When evaluated in vivo, the unformulated d-enantiomers aggregated when injected under the skin of mice, but micelle encapsulated peptides were well absorbed. Pegylated micelle formulated peptides were investigated for their potential as therapeutic agents for treating high-density infections in a murine cutaneous abscess model. Formulated peptide 73 reduced abscess size by 36% and bacterial loads by 2.2-fold compared to the parent peptide aurein 2.2Δ3. Micelle encapsulated peptides 73c and D-73 exhibited superior activity, further reducing abscess sizes by 85% and 63% and lowering bacterial loads by 510- and 9-fold compared to peptide 73.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Antimicrobial Cationic Peptides/administration & dosage , Antimicrobial Cationic Peptides/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Staphylococcal Skin Infections/drug therapy , Animals , Drug Compounding , Female , Humans , Methicillin-Resistant Staphylococcus aureus/physiology , Mice , Micelles , Microbial Sensitivity Tests , Phospholipids/chemistry , Polyethylene Glycols/chemistry , Staphylococcal Skin Infections/microbiology
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