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Regulation of lysyl oxidase expression in THP‐1 cell‐derived M2‐like macrophages
Author(s) -
Takemoto Ryuhei,
Kamiya Tetsuro,
Atobe Taku,
Hara Hirokazu,
Adachi Tetsuo
Publication year - 2021
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29911
Subject(s) - lysyl oxidase , gene knockdown , stat3 , transcription factor , foxo1 , microbiology and biotechnology , chemistry , biology , signal transduction , cancer research , biochemistry , extracellular matrix , gene
Lysyl oxidase (LOX) is a copper‐containing enzyme and its overexpression in tumor tissues promote tumor metastasis through the crosslinking of extracellular matrix. Our previous report demonstrated that LOX expression is significantly increased in human leukemic THP‐1 cell‐derived M2‐like macrophages, and histone modification plays a key role in its induction. However, the rigorous mechanism of LOX regulation remains unclear. In this study, we investigated the role of functional transcription factors, hypoxia‐inducible factor 1α (HIF1α), signal transducer and activator of transcription 3 (STAT3) and forkhead box O1 (FOXO1) in LOX regulation in M2‐like macrophages. HIF1α expression was significantly increased in M2‐like macrophages, and HIF1α inhibitor, TX402, suppressed LOX induction. The significant STAT3 activation was also observed in M2‐like macrophages. Additionally, LOX induction was canceled in the presence of STAT3 inhibitor, S3I‐201, suggesting that HIF1α and STAT3 pathways play a critical role in LOX induction. On the other hand, our ChIP results clearly indicated that the enrichment of FOXO1 within the lox promoter region was dramatically decreased in M2‐like macrophages. In this context, knockdown of FOXO1 further enhanced LOX induction. LOX induction and HIF1α binding to the lox promoter region were suppressed in FOXO1‐overexpressed cells, suggesting that the FOXO1 binding to the lox promoter region counteracted HIF1α binding to that region. Overall, the present data suggested that both of HIF1α and STAT3 were required for LOX induction in M2‐like macrophages, and loss of FOXO1 within the lox promoter region facilitated HIF1α binding to that region which promoted LOX induction.