Abstract
DDX3X is a multifunctional RNA helicase with documented roles in different cancer types. Here, we demonstrate that DDX3X plays an oncogenic role in breast cancer cells by modulating the cell cycle. Depletion of DDX3X in MCF7 cells slows cell proliferation by inducing a G1 phase arrest. Notably, DDX3X inhibits expression of Kruppel‐like factor 4 (KLF4), a transcription factor and cell cycle repressor. Moreover, DDX3X directly interacts with KLF4 mRNA and regulates its splicing. We show that DDX3X‐mediated repression of KLF4 promotes expression of S‐phase inducing genes in MCF7 breast cancer cells. These findings provide evidence for a novel function of DDX3X in regulating expression and downstream functions of KLF4, a master negative regulator of the cell cycle.
Highlights
DDX3X is a multifunctional RNA helicase with documented roles in different cancer types
DDX3X directly interacts with Kruppel-like factor 4 (KLF4) mRNA and regulates its splicing
We show that DDX3X is required for efficient proliferation of MCF7 breast cancer cells and for their progression through the cell cycle, into S phase
Summary
DDX3X is a multifunctional RNA helicase with documented roles in different cancer types. We show that DDX3X-mediated repression of KLF4 promotes expression of S-phase inducing genes in MCF7 breast cancer cells. These findings provide evidence for a novel function of DDX3X in regulating expression and downstream functions of KLF4, a master negative regulator of the cell cycle. DEAD-box proteins function as transcriptional regulators [4] and interact with spliceosome components [5,6] They mediate ribosome biogenesis [7], RNA export [8], translation initiation and termination [9,10,11] and mRNA degradation [12]. DDX3X is predominantly localized within the cytoplasm, which is consistent with a translational regulation function [14], evidence supporting nuclear functions of the helicase (including roles in transcription, pre-mRNA splicing, and mRNA export) exists [14,16]
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