Context-dependent T-BOX transcription factor family: from biology to targeted therapy

Abstract

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor immune microenvironment (TIME) and the newly arising questions that remain unresolved. This review will help in systematically and comprehensively understanding the vital role of the T-BOX transcription factor family in tumor physiology, pathology, and immunity. The intention is to provide valuable information to support the development of T-BOX-targeted therapy.

Fig. 1

Domain structure and binding profile of human T-BOX transcription factors. T-BOX family members are classified into five subfamilies and have the same T-BOX domain sequence, which is an evolutionarily conserved DNA-binding motif and a representative signature of the T-BOX family. In addition to the shared T-BOX domain, T-BOX members have specific structural domains that result in functional differences. The diagram shows the DNA-binding domain (T-BOX, blue box), inhibitory domains (grey box), activation domain (red box), +2a splicing variant (green box), and nuclear localization sequence (black box). The chromosomal positions and the domain structures of T-BOX members have been ascertained. The predicted T-BOX binding profiles were obtained from the JASPAR public database

Fig. 2

Dysregulation of T-BOX genes in pan-cancers. Overview of expression of T-BOX family members in pan-cancers. The regulation of the T-BOX family in different types of cancers is indicated in this figure. Red font indicates that the T-BOX member is up-regulated in the cancerous tissue compared to that in the corresponding para-cancerous tissue; conversely, grey font indicates that the T-BOX member is down-regulated in the cancerous tissue compared to that in the corresponding para-cancerous tissue. Data were analyzed using the GEPIA software (Gene Expression Profiling Interactive Analysis; cancer-pku.cn), which helps in analysis of the expression levels of T-BOX mRNAs

Fig. 3

Binding of T-BOX transcription factors binding with other molecules to exert synergistic effects. T-BOX molecules recruit several molecules to form synergistic complexes during physiological and cancer progression. The T-BOX complexes in physiological development: during heart development, TBX5 binds to GATA4 and NKX2.5 to form complexes, TBX1 binds to SETD7 and BAF60a to synergistically promote WNT5A expression, and TLE1/3 recruits NuRD binding to TBX20 to form a complex. TBX2 binds to Microphthalmia-associated transcription factor (MITF) to upregulate Cyclin D1 (CCND1) expression and promote melanocyte proliferation. In lung development, TBX2 binds to the NuRD complex [including HDAC1/2 and DNA-binding protein 4 (CHD4)], Chromobox3 (CBX3), and High Mobility Group Box 2 (HMGB2) to synergistically promote the expression of anti-apoptotic genes such as Cellular Communication Network Factor 4 (CCN4) and Interleukin 33 (IL33), thereby promoting the proliferation of mesenchymal progenitors. In addition, in 293T cells, TBX18 binds to different molecules to enhance transcriptional promotion [Core-Binding Factor Subunit Beta (CBFB), Chromodomain Helicase DNA Binding Protein 7 (CHD7), and IKAROS Family Zinc Finger 2 (IKZF2)] or alleviate transcriptional repression [Nuclear Receptor Coactivator 5 (NCOA5) and Strawberry Notch Homolog 2 (SBNO2)]. T-BOX complexes in tumors: in breast cancer cells, TBX2 binds to CoREST protein complexes [including LSD1, ZNF217, histone deacetylase1/2 (HDAC1/2), and RCOR1] or G9A, PRC2, and HP1/KAP1, which synergistically suppress oncogenes (CST6 and NDGR1) and promote tumor growth through epigenetic histone mediation. TBX2 binds to PRC1.1 complexes (including SKP1, BCORL1, PCGF1, BCOR, and KDM2B) and NCOR1/2 and exerts proliferative effects on melanoma cells. YAP1 and TBX5 form a complex with β-catenin and activate BCL2 Like 1 (BCL2L1) and Baculoviral IAP Repeat Containing 5 (BIRC5), thereby enhancing the anti-apoptotic effect of tumor cells. In hepatocellular carcinoma cells, TBX19 forms a transcriptional complex with PRMT1, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of Mitochondrial Fission Factor (MFF), which reduces ROS production and prevents ROS-mediated degradation of the pluripotent transcription factor OCT4, leading to enhanced tumor formation and cellular self-renewal

Fig. 4

T-BOX transcription factors act as critical nodes in tumor metastasis. T-BOX members serve as master tumor activators or suppressors to transcriptionally regulate key downstream targets or signaling pathways in tumor metastasis. The dotted line indicates positive feedback. T-BOX primarily influences tumor progression by promoting or inhibiting epithelial–mesenchymal transition (EMT). Activator: TBXT leads to pro-EMT gene expression (Snail, vimentin, N-cadherin, and fibronectin) via transcriptional activation of YAP1, MMP12, SOX5, and IL-8/IL-8R. TBX2 directly inhibits PTEN, induces EMT-related gene expression, and reduces E-cadherin expression. TBX3 expression is regulated by PKCα/β and the TROY/PI3K/AKT/TBX3 axis. TBX3 promotes SLUG and TWIST1 expression, represses PTEN, and upregulates EMT related gene expression. TBX15 promote tumor metastasis through the NF-kB pathway and form a positive feedback loop. The epidermal growth factor (EGF)/ EGF receptor (EGFR) signaling pathway upregulates TBX19 expression via the ERK/NF-kb axis as well as KRAS mutations, and TBX19 upregulates EGFR and Rac expression to promote cancer metastasis, forming a positive feedback loop. Suppressor: miR6727-5p inhibits TBX1 expression, and TBX1 suppresses cancer cell migration and invasion by downregulating the expression of EMT-related genes (TWIST, Snail, and SLUG) and MMPs (MMP12, MMP9, and MMP14). TBX5 upregulates MTSS I-BAR Domain Containing 1 (MTSS1) expression and inhibits Metastasis Associated 1 Family Member 2 (MTA2) expression, exerting its inhibitory effect on cancer cell metastasis

Fig. 5

T-BOX transcription factors act as critical nodes in tumor progress. T-BOX members serve as master tumor activators or suppressors as they transcriptionally regulate key downstream targets or signaling pathways, thereby controlling the progression of cancer, including stemness, apoptosis, proliferation and growth, and therapy resistance. A Activator: TBX2 expression was regulated by NRAGE and PI3K signaling. TBX2 and TBX3 enable cells to bypass senescence via the p14^ARF/p19^ARF-p53-p21 signaling pathway and inhibit apoptosis. TBX3 expression was inhibited by miR-206/miR-137 and WNT/β-catenin signaling pathway. TBX3 induces the CSC phenotype by regulating NODAL/ACTIVIN signaling. Suppressor: TBX1 inhibits phosphorylation in AKT and ERK pathways and promotes the expression of the pro-apoptotic genes BIM, TRAIL, and CDC25C by upregulating AKAP12, THRB, ABI3BP, PTPRQ, and PHLPP2 expression, thereby inducing G2/M cell cycle arrest and apoptosis. TBX5 induces apoptosis by targeting extrinsic pathways (TNFα /TNFRSF10B/TNFRSF1A/TNFRSF25-Caspase8), thereby enhancing the expression levels of PARP and apoptotic gene BAX and the Granzyme A signaling cascade; B Activator: TBX2 recruits HDAC and interacts with MyoD and myogenin to promote tumor progression. TBX3 recruits PRC2 and HDAC chromatin modification complexes to suppress p57^KIP2 expression. Suppressor: TBX3 activates COL1A2 or inhibits the PLD1/YAP axis to inhibit tumor progression. TBX20 inhibits tumor growth inhibition by binding to the intermediate structural domains of Ku70 and Ku80, which inhibit NHEJ-mediated DNA repair. PDZRN3 mediates degradation of TBX20; C TBXT increases tumor resistance by inhibiting SIRT1 expression and the p21/Cyclin D1/pRb pathway. TBX15 expression is inhibited by miR-212-5p, which is regulated by the NF-kb axis, and this process results in an increase in tumor resistance via the miR-152/ Kinesin Family Member 2 C (KIF2C) /PKM2 pathway

Fig. 6

Regulatory mechanisms of T-BET and EOMES in immune microenvironment. A T-BET is involved in functioning of various immune cells, including T cells, B cells, DCs, ILC, and NK cells. T cells: T-BET is induced via signaling downstream of TCR and STAT1/4. STAT1 is activated by IFNγR, IFNαR, IL-27R, and IL-21R signaling. STAT4 is activated by IL-12R signaling. T-BET binds to genes that perform different functions in T cells, including activation (IFNγ, STAT1, and IL-12R), cell trafficking (CCL3, CXCR3, and CD11a) and immune regulation (IL-2 and IL-4). B cells: BCR or IFNγR induces T-BET via STAT1, thereby promoting IgG2a conversion and memory B cell survival. NK cells: IFNγ, IL-12, and IL-21 promote T-BET expression via the STAT pathway, and IL-15 activates the PI3K-AKT-mTORC1 signaling axis to regulate T-BET expression. The roles of T-BET in NK cells include promotion of the transcription of genes (perforin and GzmB) for mediation of cytotoxicity, upregulation of IFNγ, and induction of the expression of Zeb2 to promote NK cell maturation. S1P5 regulates the trafficking of NK cells. DCs: IFNγR signaling pathway induces T-BET expression and inhibits TNF expression; proper expression of T-BET activates TH1 cells. ILC: IL-12R signaling induces T-BET expression and promotes development of IFNγ and NKp46-positive subset of cells; B EOMES is involved in functioning of various immune cells, including CD4/8⁺ T cells, NK cells, and Treg cells. CD8⁺ T cells: EOMES expression in CD8⁺ T cells is regulated by multiple signaling pathways (TCR, NF-kB, and IL-4R). EOMES promotes IFNγ and BCL expression to maintain survival and function of memory T cells. Treg cells: EOMES affects the chemotaxis of Treg via the NK-kB-CCL20-CCR6 pathway. CD4⁺ T cells: overexpression of EOMES promotes IFNγ and IL-10 production. NK cells: IL-15 induces CD122 expression via upregulation of EOMES, thereby promoting the proliferation of NK cells. In the tumor microenvironment, TGF-β inhibits EOMES expression by binding to SMAD3. EOMES inhibits CD49a (marker of ILCs) expression and induces CD49b (marker of NK cells) expression