Jinlong Yin,1,2,* Gunwoo Park,1,2,* Jeong Eun Lee,1,3,* Eun Young Choi,2,* Ju Young Park,1,3 Tae-Hoon Kim,1,2 Nayun Park,1,3 Xiong Jin,4 Ji-Eun Jung,2,4 Daye Shin,1,3 Jun Hee Hong,1,2 Hyunggee Kim,4 Heon Yoo,1,2 Seung-Hoon Lee,1,2 Youn-Jae Kim,2 Jong Bae Park1,2 and Jong Heon Kim1,3
1 Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea
2 Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea
3 Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea
4 Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
*These authors contributed equally to this work.
Correspondence to: Jong Heon Kim PhD
Correspondence may also be addressed to: Jong Bae Park PhD, Youn-Jae Kim PhD
Summary
Upregulation of microRNA-21 (miR-21) is known to be strongly associated with the proliferation, invasion, and radio-resistance of glioma cells. However, the regulatory mechanism that governs the biogenesis of miR-21 in glioma is still unclear. Here, we demonstrate that the DEAD-box RNA helicase, DDX23, promotes miR-21 biogenesis at the post-transcriptional level. The expression of DDX23 was enhanced in glioma tissues compared to normal brain, and expression level of DDX23 was highly associated with poor survival of glioma patients. Specific knockdown of DDX23 expression suppressed glioma cell proliferation and invasion in vitro and in vivo, which is similar to the function of miR-21. We found that DDX23 increased the level of miR-21 by promoting primary-to-precursor processing of miR-21 through an interaction with the Drosha microprocessor. Mutagenesis experiments critically demonstrated that the helicase activity of DDX23 was essential for the processing (cropping) of miR-21, and we further found that ivermectin, a RNA helicase inhibitor, decreased miR-21 levels by potentially inhibiting DDX23 activity and blocked invasion and cell proliferation. Moreover, treatment of ivermectin decreased glioma growth in mouse xenografts. Taken together, these results suggest that DDX23 plays an essential role in glioma progression, and might thus be a potential novel target for the therapeutic treatment of glioma.
DDX23, glioma, miR-21, miRNA biogenesis