The multi-faceted functioning portrait of LRF/ZBTB7A

Abstract

Transcription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A's orchestrated action.

Keywords: Adipogenesis; Apoptosis; Glycolysis; Hematopoietic stem cell differentiation; Oncogene; Thymic insulin expression; Tumor-suppressor gene; Zinc finger and BTB domain transcription factor.

Fig. 1

LRF/ZBTB7A regulates hematopoiesis and lymphoid development. LRF/ZBTB7A contribution in specific stages of cell differentiation is indicated. Abbreviations: HSC, hematopoietic stem cell; CMP, common myeloid progenitors; BFU-E, burst-forming unit-erythroid; CFU-E, colony-forming unit-erythroid; ProE, proerythroblasts; BasoE, basophilic erythroblasts; PolyE, polychromatophilic erythroblasts; OrthoE, orthochromatic erythroblasts; RBC, matured erythrocytes; CLP, common lymphoid progenitors; ProB, progenitor B cell; PreB, precursor B cell; DN T cell, double negative or CD4^-/8^- negative; DP T cell, double positive or CD4⁺/8⁺ positive; CD4⁺ single positive expressing Thpok (T-helper inducing POZ/Krüppel-like factor); CD8⁺ single positive expressing the Runx3; FOB, follicular B cells; MZB, marginal zone B cells; GCΒ, germinal center B cells

Fig. 2

LRF/ZBTB7A’s silencing compromises Warburg effect and induces apoptosis in cancer cells. The inhibition of aerobic glycolysis and concomitant activation of oxidative phosphorylation (OXPHOS) is promoted by the LRF/ZBTB7A’s silencing and the subsequent activation of the expression and phosphorylation of p53, leading thus to compromised Warburg effect in cancer cells. Furthermore, LRF/ZBTB7A’s silencing induces apoptosis in cancer cell lines by mediating both known apoptotic pathways (intrinsic and extrinsic) as well as their cross-talk. That is, upon LRF/ZBTB7A’s silencing and the subsequent activation of p53, the pro-apoptotic Bcl-2 family proteins as well as AIF are activated and promote cytochrome c release from mitochondria and subsequent activation of caspase-9 and caspase-3 (intrinsic apoptotic pathway). Meanwhile, LRF/ZBTB7A’s silencing promotes the expression of the Fas receptor (death receptor), leading to the activation of the downstream caspase-10 and caspase-8 and leading thus to activation of the extrinsic apoptotic pathway. In addition, caspace-8 further enhances the activation of Bcl2 family members, as well as the activation of caspase-9 and caspase-3 supporting the hypothesis that LRF/ZBTB7A, besides affecting both apoptotic pathways, potentially mediates the cross-talk between the intrinsic and extrinsic apoptotic pathways in cancer cells (in red color are cellular processes inhibited and in green color are cellular processes activated by LRF/ZBTB7A silencing). Abbreviations: AIF, apoptosis inducing factor; FasR, Fas receptor; G6PDH, glucose-6-phosphate dehydrogenase; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; SCO2, cytochrome c oxidase 2; TIGAR, TP53-induced glycolysis and apoptosis regulator

Fig. 3

LRF/ZBTB7A switches 3T3-L1 preadipocytes’ fate from cellular proliferation to terminal differentiation. Human LRF/ZBTB7A expression in 3T3-L1 preadipocytes promotes cell growth arrest at the stage of mitotic clonal expansion via inhibition of Sp1-dependent activation of cyclin A, cyclin-dependent kinase 2, and p107, while indirectly (via E2F-4 inhibition] activates PPARγ and aP2 transcription factors, known to be involved in terminal differentiation of 3T3-L1 cells into adipocytes (in red color are cellular processes inhibited and in green color are cellular processes activated by LRF/ZBTB7A expression). Abbreviations: aP2, adipocyte fatty acid-binding protein; E2F-4, E2F transcription factor 4; PPARγ, peroxisome proliferator-activated receptor gamma; Sp1, specificity protein 1