Role of transcription factor FOXM1 in diabetes and its complications (Review)

Abstract

Diabetes mellitus is a chronic metabolic disease commonly associated with complications such as cardiovascular disease, nephropathy and neuropathy, the incidence of which is increasing yearly. Transcription factor forkhead box M1 (FOXM1) serves an important role in development of diabetes and its complications. The present study aimed to review the association between FOXM1 with pathogenesis of diabetes and its complications. FOXM1 may be involved in development and progression of diabetes and its complications by regulating cell biological processes such as cell cycle, DNA damage repair, cell differentiation and epithelial‑mesenchymal transition. FOXM1 is involved in regulation of insulin secretion and insulin resistance, and FOXM1 affects insulin secretion by regulating expression of insulin‑related genes and signaling pathways; FOXM1 is involved in the inflammatory response in diabetes, and FOXM1 can regulate key genes associated with inflammatory response and immune cells, which in turn affects occurrence and development of the inflammatory response; finally, FOXM1 is involved in the regulation of diabetic complications such as cardiovascular disease, nephropathy and neuropathy. In summary, the transcription factor FOXM1 serves an important role in development of diabetes and its complications. Future studies should explore the mechanism of FOXM1 in diabetes and find new targets of FOXM1 as a potential treatment for diabetes and its complications.

Keywords: cardiovascular disease; diabetes; forkhead box M1; nephropathy; neuropathy.

Figure 1

Diabetic complications. Diabetes develops a variety of complications, including nephropathy, diabetic retinopathy, diabetic cardiovascular disease, diabetic erectile dysfunction, diabetic foot ulcers, and diabetic neuropathy.

Figure 2

FOXM1/PLK1/CENP-A pathway enhances adaptive β-cell proliferation. Adaptive β-cell proliferation contributes to the maintenance of functional β-cell mass in mice and humans. Growth factor signaling regulates mitotic cell cycle progression via the FOXM1/PLK1/CENP-A pathway, a critical component in the β-cell adaptive response. FOXM1, forkhead box M1; PLK1, Polo-like kinases; CENP-A, centromere protein A.

Figure 3

FOXM1 is involved in regulation of diabetes-related inflammatory responses. FOXM1 is involved in the pathogenesis of diabetes by regulating the expression of inflammation-associated mediators IL-1, IL-6, TNF-α, and cytokines MCP-1, CCL2, and CX3CL1. In addition, FOXM1 regulates certain inflammation-related signaling pathways, such as Wnt/β-catenin, JAK/STAT, NF-κB, TGF-β1/Smad3, PI3K/AKT/mTOR and P38MAPK. FOXM1, forkhead box M1; MCP-1, monocyte chemotactic protein-1; CCL2, chemokine (C-C motif) ligand 2; CX3CL1, C-X3-C motif chemokine ligand 1; Th, T helper.

Figure 4

FOXM1 may be involved in diabetic nephropathy by regulating signaling pathways such as NF-κB/NLRP3 and Wnt/β-catenin. FOXM1 inhibits diabetic kidney injury by regulating expression of SIRT4 and promotes diabetic kidney tissue repair. FOXM1 activates β-catenin, Cyclin D1 and c-myc genes, inhibits the expression of p21 and p27 and induces metanephric tubule regeneration. FOXM1, forkhead box M1; SIRT4, sirtuin; IP, intraperitoneal; STZ, streptozotocin; I/R, ischemia reperfusion; AKI, Acute kidney injury.

Figure 5

Schematic diagram of the signaling pathway of YAP1/FOXM1 activity in the induction of cardiomyocyte hypertrophy and fibrosis. Under hyperglycemia stress, YAP1 is activated in cardiomyocytes following reduced inactivating phosphorylation of YAP1. High glucose also increases activation of YAP1. Elevated YAP1 leads to increased AKT phosphorylation, thus promoting AKT activity. Increased AKT mediates inactivation of FOXM1. Upregulated YAP1 leads to aberrant FOXM1 accumulation within the cardiomyocyte. This elevated FOXM1 promotes pathological remodeling of cardiomyocytes, leading to cardiomyocyte hypertrophy and fibrosis. YAP, Yes-associated protein 1; FOXM1, forkhead box M1; p, phosphorylated; BNP, brain natriuretic peptide; SMA, smooth muscle actin.

Figure 6

Molecular mechanisms of FOXM1-mediated inflammatory factors (SEMA3C, STAT3, TNF) in undamaged oral mucosa, skin and DFUs models. FOXM1 activates transcription of SEMA3C, thus enhancing M2 polarization, which accelerates wound healing in DFU. FOXM1 demonstrates a similar wound-activated signature of genes involved in differentiation, cytokines and intermediate filaments. Inhibition of FOXM1, STAT3 and TNFα regulators results in lack of immune-cell activation, proliferation and survival in DFU, contributing to dysregulated inflammatory response and inhibition of wound healing. FOXM1, forkhead box M1; SEMA3C, semaphorin 3C; DFU, diabetic foot ulcer.