Open AccessRunx3 regulates iron metabolism via modulation of BMP signalling
Author(s) -
Kim HyunYi,
Lee JongMin,
Lee YouSoub,
Li Shujin,
Lee SeungJun,
Bae SukChul,
Jung HanSung
Publication year - 2021
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.13138
Subject(s) - hepcidin , bone morphogenetic protein 6 , biology , angiogenesis , microbiology and biotechnology , transcription factor , bone morphogenetic protein , downregulation and upregulation , cancer research , bone morphogenetic protein 7 , gene , immunology , biochemistry , inflammation
Objectives Runx3, a member of the Runx family of transcription factors, has been studied as a tumour suppressor and key player of organ development. In a previous study, we reported differentiation failure and excessive angiogenesis in the liver of Runx3 knock‐out (KO) mice. Here, we examined a function of the Runx3 in liver, especially in iron metabolism. Methods We performed histological and immunohistological analyses of the Runx3 KO mouse liver. RNA‐sequencing analyses were performed on primary hepatocytes isolated from Runx3 conditional KO (cKO) mice. The effect of Runx3 knock‐down (KD) was also investigated using siRNA‐mediated KD in functional human hepatocytes and human hepatocellular carcinoma cells. Result We observed an iron‐overloaded liver with decreased expression of hepcidin in Runx3 KO mice. Expression of BMP6, a regulator of hepcidin transcription, and activity of the BMP pathway were decreased in the liver tissue of Runx3 KO mice. Transcriptome analysis on primary hepatocytes isolated from Runx3 cKO mice also revealed that iron‐induced increase in BMP6 was mediated by Runx3. Similar results were observed in Runx3 knock‐down experiments using HepaRG cells and HepG2 cells. Finally, we showed that Runx3 enhanced the activity of the BMP6 promoter by responding to iron stimuli in the hepatocytes. Conclusion In conclusion, we suggest that Runx3 plays important roles in iron metabolism of the liver through regulation of BMP signalling.