title: The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression.
abstract: Posttranscriptional maturation is a critical step in microRNA (miRNA) biogenesis that determines mature miRNA levels. In addition to core components (Drosha and DGCR8 [DiGeorge syndrome critical region gene 8]) in the microprocessor, regulatory RNA-binding proteins may confer the specificity for recruiting and processing of individual primary miRNAs (pri-miRNAs). Here, we identify DDX1 as a regulatory protein that promotes the expression of a subset of miRNAs, including five members in the microRNA-200 (miR-200) family and four miRNAs in an eight-miRNA signature of a mesenchymal ovarian cancer subtype. A majority of DDX1-dependent miRNAs are induced after DNA damage. This induction is facilitated by the ataxia telangiectasia mutated (ATM)-mediated phosphorylation of DDX1. Inhibiting DDX1 promotes ovarian tumor growth and metastasis in a syngeneic mouse model. Analysis of The Cancer Genome Atlas (TCGA) reveals that low DDX1 levels are associated with poor clinical outcome in patients with serous ovarian cancer. These findings suggest that DDX1 is a key modulator in miRNA maturation and ovarian tumor suppression.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Cecil
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guohui
authors.initials: G
authors.lastname: Wan
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Luqing
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: asood@mdanderson.org.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: xzhang12@mdanderson.org.
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: xlu2@mdanderson.org.
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; C541494:DDX1 protein, mouse; C086252:DDX1 protein, human; D053487:DEAD-box RNA Helicases