Krüppel-like factors family in health and disease

Abstract

Krüppel-like factors (KLFs) are a family of basic transcription factors with three conserved Cys2/His2 zinc finger domains located in their C-terminal regions. It is acknowledged that KLFs exert complicated effects on cell proliferation, differentiation, survival, and responses to stimuli. Dysregulation of KLFs is associated with a range of diseases including cardiovascular disorders, metabolic diseases, autoimmune conditions, cancer, and neurodegenerative diseases. Their multidimensional roles in modulating critical pathways underscore the significance in both physiological and pathological contexts. Recent research also emphasizes their crucial involvement and complex interplay in the skeletal system. Despite the substantial progress in understanding KLFs and their roles in various cellular processes, several research gaps remain. Here, we elucidated the multifaceted capabilities of KLFs on body health and diseases via various compliable signaling pathways. The associations between KLFs and cellular energy metabolism and epigenetic modification during bone reconstruction have also been summarized. This review helps us better understand the coupling effects and their pivotal functions in multiple systems and detailed mechanisms of bone remodeling and develop potential therapeutic strategies for the clinical treatment of pathological diseases by targeting the KLF family.

Keywords: Krüppel‐like factors (KLFs); bone destruction diseases; bone homeostasis; energy metabolism; epigenetic modification; systemic diseases.

FIGURE 1

Protein structure and transcriptional coregulator of KLF family members. KLF protein has three conserved DNA‐binding Cys2/His2 zinc finger domains in C‐terminal regions and various protein interaction domains in N‐terminal regions. KLF family is grouped according to their shared domain architectures: (1) Group 1: KLF 3, 8, and 12 contain a PVDLS domain and bind to CtBP; (2) Group 2: KLF1, 2, 4, 5, 6, and 7 contain S/T‐rich or P‐rich LCRs; (3) Group 3: KLF9, 10, 11, 13, 14, and 16 contain SID.

FIGURE 2

Multifaceted roles of KLFs in health and diseases across multiple systems. Nervous system: KLF4 activates the Nrf2/Trx1 pathway to protect neuro in astrocyte. KLF8 regulates the expression of met and p53 in purkinje cells. KLF8 also stimulates the Wnt/β‐catenin signaling pathway in the primary neuronal cells to impact the progression of Alzheimer's disease. KLF15 inhibits the transcription of the rhodopsin and IRBP in retina. Cardiovascular system: KLF2 enhances endothelial nitric oxide synthase uncoupling through the Nrf2/HO‐1 pathway in cases of endothelial injury to improve cell viability, decrease LDH release, and reduce the oxidative stress response. KLF4 modulates Runx2 expression to enhance the arterial medial calcification. KLF5 could activate Cyclin D1 and suppress p21 to repress apoptosis to stimulate vascular remodeling. KLF14 regulates miR‐27a to diminish lipoprotein lipase expression to inhibit atherosclerosis, as well as suppresses the NF‐κB signaling pathway to restrain endothelial inflammation. KLF10 alters Pten/Akt signaling to induce cardiomyocyte apoptosis. KLF15 regulates the expression of ANP and BNP in response to heart pressure. Respiratory system: LOX‐1/TGF‐β1/KLF6 signaling pathway is involved in EMT in human bronchial epithelial cells. Digestive system: KLF6 binds to the promoter region of Beclin1 and inhibits its transcription, as well as activates the mTOR/ULK1 pathway to protect the liver. KLF2 upregulates CD36 expression that is associated with liver steatosis. Endocrine system: KLF11 inhibits caveolin‐1 gene expression in response to cholesterol signals. Urinary system: KLF15 increases the expression of regenerative genes such as adrenoreceptor alpha 1A in Xenopus laevis to promote nephric tubule regeneration. Reproductive system: KLF12 activates AKT signaling and promotes CCND1 expression, contributing to tumor growth in human endometrial cancer. KLF15 promotes the transcription of TWIST2 to facilitate the process of EMT. KLF12 inhibits Nur77 expression to restrain the decidualization of human endometrial stromal cells. KLF16 suppresses the expression of endometrial CYP1A1 that is associated with endometriosis.

FIGURE 3

Glycometabolism model involving KLFs in bone homeostasis. Pyruvate produced in glycometabolism could suppress hydrogen peroxide‐induced generation of intracellular ROS in OBs. KLF15 and KLF14 may promote GLUT and InsR, facilitating glucose uptake to supply more ATPs. ATPs produced by oxidative phosphorylation upregulate OB genes such as BMP2, MMP13, Col3a1, Ctsk, Flt1, and Bgn to enhance osteogenesis and increase intracellular calcium concentration, in turn promoting the nuclear translocation of NFATc1 to enhance BMMSC proliferation. CREB induces the transcription of Ppargc1b in response to ROS during OC differentiation. Moreover, Myc induces the transcription of ERRα, which cooperates with NFATc1 to facilitate osteoclastogenesis. Increased iron is transported by TfR1, inducing mitochondrial respiration and facilitating OC differentiation.

FIGURE 4

The coupling effects between KLFs and ncRNAs during bone remodeling. MiR‐21‐5p derived from BMMSCs inhibits KLF3 to enhance OB proliferation. Osteocyte‐derived exosomal miR‐218, which activates the Wnt signaling pathway and induces Runx2, is suppressed in osteocytes due to myokine secreted by muscles, resulting in the downregulation of osteoblastic differentiation. MiR‐197‐3p represses KLF10 expression, thereby inhibiting OB differentiation and disrupting the metabolic balance of bone. LncRNA LINC02381 suppresses osteogenic differentiation of human umbilical cord blood‐derived MSCs by sponging miR‐21 to enhance the inactivation of the Wnt/β‐catenin pathway mediated by KLF12. SNHG15 sponges miR‐7 targeting KLF4 and lncRNA MEG3 sponges miR‐9‐5p targeting KLF4, thereby inhibiting ECM degradation and cell apoptosis. lnc‐HLA‐DQA1‐5, lnc‐RP11‐127H5.1.1‐1, and lnc‐RTN2‐1 regulate KLF2 expression by sponging miRNAs (miR‐6799‐5p, miR‐1915‐3p, miR‐6764‐5p, miR‐6796‐5p, and miR‐6895‐3p), which is involved in the occurrence and development of meniscus degeneration. Circ‐Strn3 could sponge miR‐9‐5p targeting KLF5 and Circ‐ATRNL1 could sponge miR‐153‐3p targeting KLF5 and circ‐CDK14 could sponge miR‐1183 targeting KLF5, thereby ameliorating inflammatory responses, cell apoptosis, and ECM degradation.

FIGURE 5

The detailed mechanisms of OA progression through KLFs associated signaling pathways. KLF4 and KLF2 directly bind to cartilage signature genes such as COL2A1, COL11A2, PRG4, and SOX9 to increase their expression. KLF4 and KLF2 are involved in the PKA–RAP1–MEK–CREB signaling axis, ultimately suppressing mediators of inflammation and ECM‐degrading enzymes. KLF4 transcriptionally regulates InsR, inactivating JAK2/STAT3 signaling, thus suppressing apoptosis of IL‐1β‐induced OA chondrocytes. KLF2 activates the Nrf2/ARE signaling pathway to block apoptosis of chondrocytes and matrix degradation. SNHG15 sponges miR‐7 targeting KLF4 to regulate β‐catenin, and LncRNA MEG3 sponges miR‐9‐5p targeting KLF4, thereby inhibiting ECM degradation and cell apoptosis. EGR1 activates KLF5 and β‐catenin signaling to promote cartilage degeneration and hypertrophy. Circ‐Strn3 could sponge miR‐9‐5p targeting KLF5 and CircATRNL1 could sponge miR‐153‐3p targeting KLF5 and circCDK14 could sponge miR‐1183 targeting KLF5, protecting against OA. KLF10 upregulates Acvr1 and downregulates Inhbb to inhibit the proliferation and migration of chondrocytes. KLF10 promotes the TBHP‐induced senescence and ROS production. KLF 11 inhibits the p38 MAPK signaling pathway to suppress oxidative stress and apoptosis. KLF15 activates SOX‐9 expression to promote chondrogenic differentiation of hMSCs. KLF15 could bind to the promoter region of MMP‐3 and inhibit its expression, thereby improving articular cartilage degradation in OA.

FIGURE 6

The detailed mechanisms of OS progression through KLFs associated signaling pathways. Circ‐LRP6 interacts with LSD1 and EZH2 to bind to the promoter regions of KLF2, thereby inhibiting KLF2 expression and ultimately promoting OS development. SNHG6 downregulates KLF2 to accelerate OS progression. MiR‐135a targets KLF4 to inhibit cell invasion. KLF5 enhances the expression of miR‐487a that targets NKX3, which significantly facilitates the invasion and metastasis of OS cells. KLF6 suppresses bcl‐2 and MMP‐9 and activates p21 to inhibit proliferation and invasion and enhance cell apoptosis. KCNQ1OT1 targets the miR‐3666 to promote KLF7 expression, activating Wnt/β‐catenin signaling to facilitate OS progression. MiRNA‐1236‐3p downregulates KLF8 to suppress the proliferative ability and induce apoptosis of OS cells. KLF8 binds the promoter region to inhibit the expression of miR‐429, targeting SOX2 to mediate cancer stem cell‐like features. MiR‐378 and miR‐652 target KLF9 to promote the cell proliferation of OS. Circ_0078767 targets miR‐889 to enhance KLF9 expression, ultimately inhibiting OS progression.