Bipartite regulation of cellular communication network factor 2 and fibroblast growth factor 1 genes by fibroblast growth factor 1 through histone deacetylase 1 and fork head box protein A1

Journal of Cell Communication and Signaling

article

Elseoudi, Abdellatif¹  Nishida, Takashi¹  Mizukawa, Tomomi¹  Hattori, Takako¹  Kawata, Kazumi¹  Taha, Eman A.⁴  Takigawa, Masaharu⁷  Kubota, Satoshi¹ 

[1] Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University;CHU Sainte-Justine Hospital Research Center, University of Montreal;Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University;Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University;Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University;Department of Biochemistry, Faculty of Science, Ain Shams University;Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University

关键词: FGF-1;    CCN2;    Osteoarthritis;    Chondrocytes;    Cartilage;   

DOI  :  10.1007/s12079-020-00600-4

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

Fibroblast growth factor 1 (FGF-1) is the first FGF family member, and it induces proliferation of fibroblasts and other types of the cells. However, recent studies are uncovering unexpected functions of this molecule. Our previous study redefined this growth factor as a catabolic molecule produced in cartilage upon metabolic insult. Indeed, FGF-1 was found to repress the gene expression of cellular communication network factor 2 (CCN2), which protects and regenerates cartilage, amplifying its own production through positive feedback regulation. In the present study, we investigated the molecular mechanism of this bipartite CCN2 repression and FGF1 activation by FGF-1 in chondrocytes. Repression of CCN2 and induction of FGF1 in human chondrocytic cells were both partly abolished by valproic acid, an inhibitor of histone deacetylase 1 (HDAC1), indicating the involvement of chromatin remodeling by histone acetylation in this system. In contrast, RNA degradation analysis suggested no contribution of post-transcriptional regulation of the mRNA stability to the effects conferred by FGF-1. Suspecting a regulation by a specific transcription factor, we next sought a candidate in silico from a large dataset. As a result, we found fork head box protein A1 (FOXA1) as the transcription factor that bound to both CCN2 and FGF1 loci. Functional analysis demonstrated that FOXA1 silencing significantly attenuated the CCN2 repression and FGF1 induction caused by FGF1. These findings collectively indicate that the bipartite regulation by FGF-1 is enabled by the combination of chromatin remodeling by HDACs and transcriptional modulation by FOXA1 with unknown transcriptional coactivators of opposite functionalities.

【 授权许可】

CC BY