microRNA-365-targeted nuclear factor I/B transcriptionally represses cyclin-dependent kinase 6 and 4 to inhibit the progression of cutaneous squamous cell carcinoma.

Abstract

Cyclin-dependent kinases are either post-transcriptionally regulated by interacting with cyclins and cyclin-dependent kinase inhibitors or are transcriptionally regulated by transcription factors, but the latter mechanism has not been extensively investigated. Dysregulated transcription factors resulting from aberrantly expressed microRNAs play critical roles in tumor development and progression. Our previous work identified miR-365 as an oncogenic microRNA that promotes the development of cutaneous squamous cell carcinoma via repression of cyclin-dependent kinase 6, while miR-365 also targets nuclear factor I/B. However, the underlying mechanism(s) of the interaction between nuclear factor I/B and cyclin-dependent kinase 6 are unclear. In this work, we demonstrate that miR-365-regulated nuclear factor I/B transcriptionally inhibits cyclin-dependent kinases 6 and 4 by binding to their promoter regions. In vivo and in vitro experiments demonstrate that the loss of nuclear factor I/B after miR-365 expression or treatment with small interfering RNAs results in the upregulation of cyclin-dependent kinases 6 and 4. This upregulation, in turn, enhances the phosphorylation of retinoblastoma protein and tumor progression. Characterizing this transcriptional repression of cyclin-dependent kinases 6 and 4 by nuclear factor I/B contributes to the understanding of the transcriptional regulation of cyclin-dependent kinases by transcription factors and also facilitates the development of new therapeutic regimens to improve the clinical treatment of cutaneous squamous cell carcinoma.

• Authors: Liang Zhou, Yinghui Wang, Chengshan Ou, Zhixiang Lin, Jianyu Wang, Hongxia Liu, Meijuan Zhou, Zhenhua Ding
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 65 Pg. 182-91 (Aug 2015) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 26072217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• MicroRNAs
• NFI Transcription Factors
• NFIB protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Carcinoma, Squamous Cell (genetics, metabolism)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4 (metabolism)
• Cyclin-Dependent Kinase 6 (metabolism)
• Disease Progression
• Humans
• Mice
• Mice, Inbred BALB C
• MicroRNAs (genetics, metabolism)
• NFI Transcription Factors (genetics, metabolism)
• Skin Neoplasms (genetics, metabolism)