title: 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.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
authors.forename: Chengshan
authors.initials: C
authors.lastname: Ou
authors.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
authors.forename: Jianyu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropic Medicine, Southern Medical University, Guangdong, Guangzhou 510515, People's Republic of China. Electronic address: dingzh@smu.edu.cn.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Ding
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051839:NFI Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D051839:NFI Transcription Factors; C110754:NFIB protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: CDK4; CDK6; Cutaneous squamous cell carcinoma; Nuclear factor I/B; Retinoblastoma protein; miR-365