MicroRNAs (miRNAs) are small endogenous non-coding RNAs that regulate gene expression by repressing translation and/or promoting degradation of their target mRNAs. Aberrant dysregulation of mature miRNAs is commonly observed in many human cancers and can have a causative function in tumorigenesis. In the nucleus, primary miRNAs (pri-miRNAs) are first processed by the microprocessor containing RNaseIII enzyme Drosha and its cofactor DGCR8. Although the efficiency of Drosha-mediated process is crucial for determining miRNA abundance, the mechanisms for dynamic and specific regulation of miRNA biogenesis in the Drosha microprocessor are poorly understood. A better understanding of miRNA regulation is required to determine how aberrant miRNA activity mechanistically contributes to tumorigenesis and to predict therapeutic target miRNAs. Increasing evidence has shown that regulatory RNA-binding proteins may confer the specificity on the core components (Drosha and DGCR8) in the Microprocessor for recruiting and processing premature pri-miRNAs.

Here, we identified a RNA-binding protein, DEAD-box RNA helicase 1 (DDX1) as a key regulatory component in the Drosha complex, which promotes the processing of a subset of miRNAs including miR-200 family (miR-200a, -200b, -200c, -141, -429). A suppressive role of miR-200s in cancer metastasis has been well known in several cancer types such as ovarian, kidney renal and lung cancer. Inhibiting DDX1 promotes tumor burden in the previous syngeneic ovarian mouse models. Consistent with, low level of DDX1 is associated with poor clinical outcome in patients with serous ovarian cancer and kidney renal clear cell carcinoma. Interestingly, DDX1-dependent miR-200a and miR-200b were also induced after DNA damage and this induction is facilitated by the ATM-mediated phosphorylation of DDX1. These findings suggest that DDX1 may be a key modulator in miRNA maturation in response to cellular signaling pathway and that alteration of level/function of DDX1 may play an important role in tumor progression through dysregulated microRNA pathway.

Citation Format: Cecil Han, Xiongbin Lu, Xinna Zhang. The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A32.