miR-16 induction after CDK4 knockdown is mediated by c-Myc suppression and inhibits cell growth as well as sensitizes nasopharyngeal carcinoma cells to chemotherapy
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Cyclin-dependent kinase 4 (CDK4) is a member of cyclin-dependent kinase family which regulates G1 to S cell cycle transition. CDK4 activity is increased in many tumor types. Here, we report a negative automodulatory feedback loop between CDK4 and miR-16 that regulates cell cycle progression in nasopharyngeal carcinoma (NPC). By miRNA array and real-time PCR, we identified upregulation of tumor suppressor miR-16a, which inhibited cell cycle progression and sensitized NPC cells to chemotherapy. CDK4 knockdown reduced the expression of c-Myc, the latter of which directly suppresses the miR-16 expression by directly binding to the miR-16 promoter. Moreover, we found that miR-16 upregulation could reduce CDK4 expression by repressing CCND1 and thus forms a feedback loop via the CDK4/c-Myc/miR-16/CCND1 pathway. Finally, miR-16 was negatively correlated with CDK4 expression in NPC biopsies. In summary, our results define a double-negative feedback loop involving CDK4 and miR-16 mediated by c-Myc that modulates NPC cell growth and chemotherapy sensitivity.
KeywordsNPC CDK4 miR-16 c-Myc Feedback loop
This study was supported by the National Nature Science Fund of China (No. 30971438, 81102061), the New Star Plan of Pearl River Science and Technology from Guangzhou City (No. 2011J2200009), Guangdong Science and Technology Planning Project (No. 2014A020212342), Yangcheng Scholar Research Projects from Universities of Guangzhou (No. 12A011D), The Oustanding Young Teacher Training Project of Collegues and Universities in GuangDong Province (No.Yp2013136), Guangzhou Science and Technology Planning Project (No. 2013J4100035), and the Ph.D. Programs Foundation of Ministry of Education of China (No. 20134423110001)
Conflicts of interest
QJ, YZ, MZ, and XJL coordinated and performed the studies as well as assisted in the editing of manuscript. QL and RC collected the tissue samples. WF and ZL designed this study and wrote this paper.
- 27.Bar J, Gorn-Hondermann I, Moretto P, Perkins TJ, Niknejad N, Stewart DJ, Goss GD, Dimitroulakos J. miR profiling identifies cyclin-dependent kinase 6 downregulation as a potential mechanism of acquired cisplatin resistance in non-small-cell lung carcinoma. Clin Lung Cancer. 2015.Google Scholar