A double-negative feedback loop between DEAD-box protein DDX21 and Snail regulates epithelial-mesenchymal transition and metastasis in breast cancer.

DDX21, a DEAD-box protein, implicated in fundamental aspects of RNA metabolism such as gene transcription. DDX21 expression is dysregulated in cancer, but its specific contribution to tumor invasion and metastasis remains to be determined. Here, we demonstrate DDX21 down-regulation is associated with highly metastatic and poor prognosis human breast cancers. DDX21 overexpression inhibited, while DDX21 knockdown promoted epithelial-mesenchymal transition (EMT) in vitro and in vivo. Overexpression of Snail reversed DDX21 mediated inhibition of cell invasion. On the other hand, independent of its helicase activity, DDX21 suppressed Snail transcription by recruiting SUZ12 and EZH2, two core subunits of PRC2 (polycomb-repressive complex 2), to the Snail promoter. Furthermore, down-regulation of DDX21 is mediated by miR-218-5p. Surprisingly, Snail also modulates DDX21 transcription. Snail overexpression decreased DDX21 transcription, whereas Snail knockdown increased DDX21 expression. These novel observations demonstrate firstly, the antagonism/double negative feedback loop between DDX21 and Snail transcription, and secondly, the crucial role of miR-218-5p in promoting EMT, acting by decreasing the ratio of DDX21/Snail. Our results identify DDX21 as a breast cancer metastasis suppressor; blocking miR-218-5p will stabilize DDX21 and epigenetically suppress Snail expression and EMT.

Zhang H ，Zhang Y ，Chen C ，Zhu X ，Zhang C ，Xia Y ，Zhao Y ，Andrisani OM ，Kong L ... -  《-》

Down-regulation of miR-129-5p via the Twist1-Snail feedback loop stimulates the epithelial-mesenchymal transition and is associated with poor prognosis in breast cancer.

Yu Y ，Zhao Y ，Sun XH ，Ge J ，Zhang B ，Wang X ，Cao XC ... -  《Oncotarget》

SREBP1, targeted by miR-18a-5p, modulates epithelial-mesenchymal transition in breast cancer via forming a co-repressor complex with Snail and HDAC1/2.

Zhang N ，Zhang H ，Liu Y ，Su P ，Zhang J ，Wang X ，Sun M ，Chen B ，Zhao W ，Wang L ，Wang H ，Moran MS ，Haffty BG ，Yang Q ... -  《-》

Distinct Ring1b complexes defined by DEAD-box helicases and EMT transcription factors synergistically enhance E-cadherin silencing in breast cancer.

Wang Y ，Sun Y ，Shang C ，Chen L ，Chen H ，Wang D ，Zeng X ... -  《Cell Death & Disease》

Snail and Slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma.

Zheng M ，Jiang YP ，Chen W ，Li KD ，Liu X ，Gao SY ，Feng H ，Wang SS ，Jiang J ，Ma XR ，Cen X ，Tang YJ ，Chen Y ，Lin YF ，Tang YL ，Liang XH ... -  《Oncotarget》