miR-22 suppresses DNA ligase III addiction in multiple myeloma

Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and e...

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Bibliographic Details
Published in:Leukemia 2019-02, Vol.33 (2), p.487-498
Main Authors: Caracciolo, Daniele, Di Martino, Maria Teresa, Amodio, Nicola, Morelli, Eugenio, Montesano, Martina, Botta, Cirino, Scionti, Francesca, Talarico, Daniela, Altomare, Emanuela, Gallo Cantafio, Maria Eugenia, Zuccalà, Valeria, Maltese, Lorenza, Todoerti, Katia, Rossi, Marco, Arbitrio, Mariamena, Neri, Antonino, Tagliaferri, Pierosandro, Tassone, Pierfrancesco
Format: Article
Language:English
Subjects:
Addictions
Apoptosis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cancer genetics
Care and treatment
Cell Proliferation
Deoxyribonucleic acid
Development and progression
DNA
DNA Damage
DNA Ligase ATP - genetics
DNA Ligase ATP - metabolism
DNA Repair
Gene expression
Gene Expression Regulation, Neoplastic
Gene regulation
Genetic aspects
Genomes
Genomic instability
Genomics
Health aspects
Humans
In vivo methods and tests
Ligases
Malignancy
Messenger RNA
MicroRNA
MicroRNAs - genetics
Multiple myeloma
Multiple Myeloma - enzymology
Multiple Myeloma - genetics
Multiple Myeloma - pathology
Poly-ADP-Ribose Binding Proteins - genetics
Poly-ADP-Ribose Binding Proteins - metabolism
Post-transcription
Prognosis
Proteins
RNA
Stability
Survival
Tumor Cells, Cultured
Viability
Xenograft Model Antitumor Assays
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Summary:Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.
ISSN:0887-6924
1476-5551
1476-5551
DOI:10.1038/s41375-018-0238-2