Regulation of lysyl oxidase expression in THP‐1 cell‐derived M2‐like macrophages

Abstract

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.

Copper in the tumor microenvironment and tumor metastasis

“…Regarding the induction of LOX in tumor-associated macrophages, we previously reported that JMJD3-mediated histone H3K27 demethylation plays a key role in its expression.‍ ( 71 ) Histone lysine demethylases, including JMJD3, are upregulated in several tumors.‍ ( 73 , 74 ) In addition, macrophage differentiation into tumor-associated M2 macrophages is regulated by JMJD3-mediated H3K27 demethylation.‍ ( 75 ) Our studies may help clarify the molecular mechanisms governing epigenetic LOX induction in the tumor microenvironment. We also demonstrated that hypoxia-inducible factor 1α (HIF1α), a well-known transcription factor induced in tumor tissues, is involved in LOX expression in tumor-associated macrophages.‍ ( 76 ) This is consistent with LOX expression increasing in the tumor microenvironment under hypoxic conditions.…”

Rab44 Deficiency Induces Impaired Immune Responses to Nickel Allergy

“…In different microenvironments, macrophages are polarized into two subtypes: classically activated macrophages (M1) or alternatively activated macrophages (M2) [ 23 , 24 ]. We used the human monocytic cell line THP-1, which is useful for studying monocyte/macrophage differentiation [ 25 , 26 ], and examined the expression levels of Rab44 compared with M1 markers, including IL-6, CD80, and NOS2, and M2 markers, including interleukin-10 (IL-10), CD206, and arginase. A real-time PCR analysis of mRNA levels revealed that Rab44 was transiently upregulated at an early phase in both M1 ( Figure 1 a, left panel and b) and M2 differentiation ( Figure 1 a, right panel and b).…”

Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

“…However, upon Cu stimulation, exosomes secreted by MΦs increase angiogenesis mediated by endothelial cells in vitro and in vivo [222]. Ryuhei Takemoto and colleagues also found that overexpression of lysyl oxidase, a Cu-containing enzyme, in human leukemic THP-1cell-derived M2 MΦs promotes tumor metastasis [223]. Therefore, immune cell cuproptosis may have a multifaceted role in TME, and we are awaiting rational animal and cellular investigations to elucidate this role.…”