The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA.
Multiple myeloma, the second most frequent hematologic tumor after lymphomas, is an incurable cancer. Recent sequencing efforts have identified the ribonuclease DIS3 as one of the most frequently mutated genes in this disease. DIS3 represents the catalytic subunit of the exosome, a macromolecular complex central to the processing, maturation and surveillance of various RNAs. miRNAs are an evolutionarily conserved class of small noncoding RNAs, regulating gene expression at post-transcriptional level. Ribonucleases, including Drosha, Dicer and XRN2, are involved in the processing and stability of miRNAs. However, the role of DIS3 on the regulation of miRNAs remains largely unknown. Here we found that DIS3 regulates the levels of the tumor suppressor let-7 miRNAs without affecting other miRNA families. DIS3 facilitates the maturation of let-7 miRNAs by reducing in the cytoplasm the RNA stability of the pluripotency factor LIN28B, a inhibitor of let-7 processing. DIS3 inactivation, through the increase of LIN28B and the reduction of mature let-7, enhances the translation of let-7 targets such as MYC and RAS leading to enhanced tumorigenesis. Our study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation.
Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20133 Milan, Italy.
Simona
S
Segalla
Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20133 Milan, Italy.
Silvia
S
Pivetti
Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy.
Katia
K
Todoerti
Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20133 Milan, Italy.
Malgorzata Agata
MA
Chudzik
Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20133 Milan, Italy.
Erica Claudia
EC
Giuliani
Dipartimento di Bioscienze, Università degli Studi di Milano, 20132 Milan, Italy.
Federico
F
Lazzaro
Molecular Histology and Cell Growth Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Science Institute, 20132 Milan, Italy.
Viviana
V
Volta
Center for Translational Genomics and Bioinformatics, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, 20132 Milan, Italy.
Dejan
D
Lazarevic
Dulbecco Telethon Institute, S. Raffaele Hospital, 20132 Milan, Italy.
Giovanna
G
Musco
Dipartimento di Bioscienze, Università degli Studi di Milano, 20132 Milan, Italy.
Marco
M
Muzi-Falconi
Department of Clinical Sciences and Community Health, University of Milan, Hematology1 CTMO, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
Antonino
A
Neri
Molecular Histology and Cell Growth Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Science Institute, 20132 Milan, Italy Dipartimento di Scienze e Innovazione Tecnologica, University of Piemonte Orientale, 15100 Alessandria, Italy.
Stefano
S
Biffo
Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20133 Milan, Italy Università Vita-Salute San Raffaele, Milan, 20132, Italy tonon.giovanni@hsr.it.
Giovanni
http://orcid.org/0000-0003-2973-5038
G
Tonon
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D063326:Exosome Multienzyme Ribonuclease Complex / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C570876:Lin28b protein, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse; D063326:Exosome Multienzyme Ribonuclease Complex; C484487:Dis3 protein, mouse; C551543:DIS3 protein, human