Krüppel-like factors in tumors: Key regulators and therapeutic avenues

Abstract

Krüppel-like factors (KLFs) are a group of DNA-binding transcriptional regulators with multiple essential functions in various cellular processes, including proliferation, migration, inflammation, and angiogenesis. The aberrant expression of KLFs is often found in tumor tissues and is essential for tumor development. At the molecular level, KLFs regulate multiple signaling pathways and mediate crosstalk among them. Some KLFs may also be molecular switches for specific biological signals, driving their transition from tumor suppressors to promoters. At the histological level, the abnormal expression of KLFs is closely associated with tumor cell stemness, proliferation, apoptosis, and alterations in the tumor microenvironment. Notably, the role of each KLF in tumors varies according to tumor type and different stages of tumor development rather than being invariant. In this review, we focus on the advances in the molecular biology of KLFs, particularly the regulations of several classical signaling pathways by these factors, and the critical role of KLFs in tumor development. We also highlight their strong potential as molecular targets in tumor therapy and suggest potential directions for clinical translational research.

Keywords: Krüppel-like factor; molecular target; signal transduction; tumor; tumor microenvironment.

Figure 1

KLFs in cancer-related signaling pathways. Krüppel-like factors (KLFs) regulate multiple signaling pathways, which is crucial in cancer progression by affecting the activity of the promoter, the phosphorylation process, and the binding ability of transcription factors. The ability of some KLFs to regulate multiple signaling pathways simultaneously suggests that they may mediate the crosstalk between signaling pathways. RHO, ras homolog gene; HDAC, histone deacetylase; ITGB1, integrin subunit beta 1; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; TSC2, tuberous sclerosis complex 2; GSK-3, glycogen synthase kinase 3; ACSM3, acyl-CoA synthetase medium chain family member 3; PTEN, phosphatase and tensin homolog; WNT, wingless/integrated; TCF1, transcription factor 1; Dvl, dishevelled proteins; G, G protein; PLC, phospholipase C; PKC, protein kinase C; NFAT, nuclear factor of activated T cells; SMRT, silencing mediator of retinoic acid and thyroid hormone receptor; AP-1, activator protein-1; NICD, NOTCH intracellular domain; CSL, [CBF-1, Su(H), Lag-1]-type transcription factors; HIF, hypoxia-inducible factor; SOX4, sex determining region Y-box 4; TGF-β, transforming growth factor beta; MAPKKK, MAP kinase kinase kinase; MAPKK, MAP kinase kinase; ERK, extracellular regulated protein kinase; JNK, c-Jun N-terminal kinase; Spred1, Sprouty-related EVH1 domain-containing protein 1; E2F1, E2F transcription factor 1.

Figure 2

KLFs have diverse effects on cancer cells and tumor microenvironment. Based on the regulation of several signaling pathways and biomolecules, Krüppel-like factors (KLFs) regulate tumor progression by affecting several processes, including the cancer stemness, cell cycle, apoptosis, angiogenesis, metastasis, and cancer inflammation. Ac-KLF5, acetylated KLF5; M1, classically activated macrophage; M2, alternatively activated macrophage.