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Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells

  
@article{APS6172,
	author = {Hai-yan Hu and Kun-peng Li and Xiu-ju Wang and Yuan Liu and Zhi-gang Lu and Rui-hong Dong and Hong-bo Guo and Mei-xia Zhang},
	title = {Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells},
	journal = {Acta Pharmacologica Sinica},
	volume = {34},
	number = {1},
	year = {2016},
	keywords = {},
	abstract = {Hai-yan HU1, #, Kun-peng LI4, #, Xiu-ju WANG2, #, Yuan LIU3, Zhi-gang LU3, Rui-hong DONG3, Hong-bo GUO3, *, Mei-xia ZHANG3, *

1Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China; 2Hematology Department of Sun Yat-Sen University, Guangzhou 501170, China; 3Hematology Department of Zhujiang Hospital of Southern Medical University, Guangzhou 510282, China; 4School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
 
Aim: To investigate the mechanisms by which berberine suppressed the proliferation of human multiple myeloma cells.

Methods: Human U266 multiple myeloma cell line was tested.  Cell proliferation, apoptosis, ultramicrostructure and secretion function were examined using Cell Counting Kit-8 (CCK8), flow cytometry (FCM), electron and fluorescence microscopy, as well as ELISA assay.  The microRNAs (miRs) and transcription factors in U266 cells were detected using arrays and verified by qRT-PCR.  EMSA and luciferase assays were used to verify the p65-dependent transactivation of miR-21 gene.

Results: Treatment of U266 cells with berberine (40−160 µmol/L) suppressed cell proliferation and IL-6 secretion in dose- and time-dependent manners.  Meanwhile, berberine dose-dependently induced ROS generation, G2/M phase arrest and apoptosis in U266 cells, and decreased the levels of miR-21 and Bcl-2.  Overexpression of miR-21 counteracted berberine-induced suppression of cell proliferation and IL-6 secretion.  In U266 cells treated with berberine (80 µmol/L), the activity of NF-κB was decreased by approximately 50%, followed by significant reduction of miR-21 level.  berberine (80−160 µmol/L) increased the level of Set9 (lysine methyltransferase) by more than 2-fold, caused methylation of the RelA subunit, which inhibited NF-κB nuclear translocation and miR-21 transcription.  In U266 cells treated with berberine (80 µmol/L), knockdown of Set9 with siRNAs significantly increased NF-κB protein level accompanying with a partial recovery of proliferation.

Conclusion: In U266 cells, berberine suppresses NF-κB nuclear translocation via Set9-mediated lysine methylation, leads to decrease in the levels miR21 and Bcl-2, which induces ROS generation and apoptosis.

 
Keywords: multiple myeloma; berberine; apoptosis; NF-κB; Set9; methylation; RelA; microRNA-21; Bcl-2; ROS
 
This paper was supported by Guangdong Science and Technology Plan (No 2012A030400012).
# The first three authors contributed equally to this work.
* To whom correspondence should be addressed.  
E-mail guohongbo7272@126.com (Hong-bo GUO); meixiaz88@yahoo.com.cn (Mei-xia ZHANG)
Received 2012-07-08    Accepted 2012-10-22},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/6172}
}