Table Info

Table 1.

TFs and their role in cancer

Name	Description	Role in cancer
NF-κB	A dimeric TF that combines NF-κB and Rel protein. It regulates the expression of several genes related to inflammation, innate and adaptive immunity and stress response.	It plays an important role in tumorigenesis, inflammation, preventing apoptosis, supporting angiogenesis and metastasis.
p53	Also known as TP53 functions as TF when forms a tetramer. It plays important role in DNA damage, cell-cycle regulation and apoptosis.	It acts as a tumour suppressor. Most tumours have mutations in the p53 gene. Mutated proteins cannot bind DNA effectively and cells lose their control on cell cycle regulation and apoptosis.
c-Myb	As an oncogenic TF, it controls the several genes related to cell proliferation, differentiation and apoptosis. It plays a key role in haematopoietic cell proliferation and lineage differentiation.	Over expression of c-Myb is noticed in breast, colon and haematopoietic cancer. In solid tumours, c-Myb is required for proliferation and in leukaemia, c-Myb controls several downstream genes necessary to maintain the proliferation of leukaemic cells.
MLL-AF9	A chimeric TF formed by chromosomal translocation of the N-terminal DNA binding part of the MLL protein (lysine-specific methyltransferase 2A located in chromosome 11) with the c-terminal part of AF9 protein (gene is located in chromosome 9). This TF can bind promoters of a wide range of proteins as well as the enhancer elements.	The RUNX1 gene (runt-related TF1) is one of the most well documented downstream targets of MLL-AF9. RUNX1 is a TF that controls granulocytic differentiation. MLL-AF9 driven overexpression of RUNX1 mediates leukemogenic transformation.
c-MYC	Oncogenic TF which is responsible to control cell proliferation and apoptosis.	Overexpression of c-MYC is observed in more than 40% of tumours. Overexpression caused by gene amplification deregulates the cell proliferation and apoptosis pathways.
STAT3	A master TF that controls the expression of several genes related to the innate and adaptive immunity. It plays an integral part to transduce the signal from receptors to the transduction factors to relocate in the nucleus.	It acts as a key player in supporting tumour microenvironment which includes maintaining hypoxic condition, blood vessels and extracellular matrix (ECM) formation, immune cells, and inflammatory cells proliferation.
AML1-ETO	A fusion protein generated by chromosomal translocation in AML. The fusion protein comprises of conserved runt homology (which is the DNA binding domain) from the hematopoietic TF RUNX1 (also known as AML1) and ETO repressor protein. It is considered as a transcriptional repressor of all RUNX1 target genes.	AML1 acts as a transcriptional activator but this fusion protein acts as a transcriptional repressor in granulocytic differentiation and drives granulocytes in the mode of continuous uncontrolled proliferation.
HIF-1	A key TF that regulates the physiological response to the low oxygen concentration or in hypoxia.	It plays a crucial role in maintaining the hypoxic tumour microenvironment by regulating several genes related to this phenomenon. Elevated expression of this TF is associated with poor prognosis and high metastasis.
AP1	It forms a heterodimer with the oncoproteins c-FOS or c-JUN and regulates genes related to the cell proliferation, differentiation, apoptosis and angiogenesis.	It acts as an oncogenic factor or tumour suppressor depending on the nature of the cell types, stage of the tumour and its genotypes.

Declarations

Acknowledgments

My sincere gratitude goes to Prof. Thomas Gonda who offered me an opportunity to contribute to this area of science. I am also grateful to Prof. Rik Thompson who inspired and helped me to move forward in the area of drug discovery and to Institute of Health and Biomedical Innovation, the Queensland University of Technology, Australia for generous support.

Author contributions

The author contributed solely to the paper.

Conflicts of interest

The author declares that there are no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Lambert M, Jambon S, Depauw S, David-Cordonnier MH. Targeting transcription factors for cancer treatment. Molecules. 2018;23:1479. [DOI]

Kirtonia A, Pandya G, Sethi G, Pandey AK, Das BC, Garg M. A comprehensive review of genetic alterations and molecular targeted therapies for the implementation of personalized medicine in acute myeloid leukemia. J Mol Med. 2020;98:1069–91. [DOI] [PubMed]

Peng X, Pentassuglia L, Sawyer DB. Emerging anticancer therapeutic targets and the cardiovascular system: is there cause for concern? Circ Res. 2010;106:1022–34. [DOI] [PubMed] [PMC]

Chang JS, Noh DY, Park IA, Kim MJ, Song H, Ryu SH, et al. Overexpression of phospholipase C-gamma1 in rat 3Y1 fibroblast cells leads to malignant transformation. Cancer Res. 1997;57:5465–8. [PubMed]

Lo Vasco VR, Leopizzi M, Di Maio V, Della Rocca C. U-73122 reduces the cell growth in cultured MG-63 ostesarcoma cell line involving Phosphoinositide-specific Phospholipases C. Springerplus. 2016;5:156. [DOI] [PubMed] [PMC]

Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18:1414. [DOI]

Gilmore TD, Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene. 2006;25:6887–99. [DOI] [PubMed]

Bennett J, Capece D, Begalli F, Verzella D, D’Andrea D, Tornatore L, et al. NF-kappaB in the crosshairs: rethinking an old riddle. Int J Biochem Cell Biol. 2018;95:108–12. [DOI] [PubMed] [PMC]

Sanz G, Singh M, Peuget S, Selivanova G. Inhibition of p53 inhibitors: progress, challenges and perspectives. J Mol Cell Biol. 2019;11:586–99. [DOI] [PubMed] [PMC]

10.

Bushweller JH. Targeting transcription factors in cancer-from undruggable to reality. Nat Rev Cancer. 2019;19:611–24. [DOI] [PubMed]

11.

Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell. 2013;152:1237–51. [DOI] [PubMed] [PMC]

12.

Ramsay RG, Gonda TJ. MYB function in normal and cancer cells. Nat Rev Cancer. 2008;8:523–34. [DOI] [PubMed]

13.

Murillo-Ortiz B, Pérez-Luque E, Malacara JM, Daza-Benítez L, Hernández-Gonzalez M, Benítez-Bribiesca L. Expression of estrogen receptor alpha and beta in breast cancers of pre- and post-menopausal women. Pathol Oncol Res. 2008;14:435–42. [DOI] [PubMed]

14.

Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013;4:1116–30. [DOI] [PubMed] [PMC]

15.

Mitra P, Pereira LA, Drabsch Y, Ramsay RG, Gonda TJ. Estrogen receptor-alpha recruits P-TEFb to overcome transcriptional pausing in intron 1 of the MYB gene. Nucleic Acids Res. 2012;40:5988–6000. [DOI] [PubMed] [PMC]

16.

Mitra P, Yang RM, Sutton J, Ramsay RG, Gonda TJ. CDK9 inhibitors selectively target estrogen receptor-positive breast cancer cells through combined inhibition of MYB and MCL-1 expression. Oncotarget. 2016;7:9069–83. [DOI] [PubMed] [PMC]

17.

Boffo S, Damato A, Alfano L, Giordano A. CDK9 inhibitors in acute myeloid leukemia. J Exp Clin Cancer Res. 2018;37:36. [DOI] [PubMed] [PMC]

18.

Yokoyama A. Transcriptional activation by MLL fusion proteins in leukemogenesis. Exp Hematol. 2017;46:21–30. [DOI] [PubMed]

19.

Ward C, Cauchy P, Walton DS, Clarke M, Blakemore D, Grebien F, et al. Ablation of MYB-dependent leukaemia phenotype in MLL-driven AML correlates with increased expression of MAFB. BioRxiv 118828 [Preprint]. 2020 [cited 2020 May 30]. Available from: https://www.biorxiv.org/content/10.1101/2020.05.27.118828v1 [DOI]

20.

Cao L, Mitra P, Gonda TJ. The mechanism of MYB transcriptional regulation by MLL-AF9 oncoprotein. Sci Rep. 2019;9:20084. [DOI] [PubMed] [PMC]

21.

Campbell CT, Haladyna JN, Drubin DA, Thomson TM, Maria MJ, Yamauchi T, et al. Mechanisms of pin ometostat (EPZ-5676) treatment-emergent resistance in MLL-rearranged leukemia. Mol Cancer Ther. 2017;16:1669–79. [DOI] [PubMed]

22.

Piha-Paul SA, Sachdev JC, Barve M, LoRusso P, Szmulewitz R, Patel SP, et al. First-in-human study of mivebresib (ABBV-075), an oral pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory solid tumors. Clin Cancer Res. 2019;25:6309–19. [DOI] [PubMed]

23.

Yin M, Guo Y, Hu R, Cai WL, Li Y, Pei S, et al. Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nat Commun. 2020;11:1833. [DOI] [PubMed] [PMC]

24.

Riveiro ME, Astorgues-Xerri L, Vazquez R, Frapolli R, Kwee I, Rinaldi A, et al. OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations. Oncotarget. 2016;7:84675–87. [DOI] [PubMed] [PMC]

25.

Gerlach D, Tontsch-Grunt U, Baum A, Popow J, Scharn D, Hofmann MH, et al. The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML. Oncogene. 2018;37:2687–701. [DOI] [PubMed] [PMC]

26.

Li H, Ban F, Dalal K, Leblanc E, Frewin K, Ma D, et al. Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor. J Med Chem. 2014;57:6458–67. [DOI] [PubMed]

27.

Huang W, Dong Z, Chen Y, Wang F, Wang CJ, Peng H, et al. Small-molecule inhibitors targeting the DNA-binding domain of STAT3 suppress tumor growth, metastasis and STAT3 target gene expression in vivo. Oncogene. 2016;35:783–92. [DOI] [PubMed]

28.

Abbehausen C. Zinc finger domains as therapeutic targets for metal-based compounds-an update. Metallomics. 2019;11:15–28. [DOI] [PubMed]

29.

Pattabiraman DR, McGirr C, Shakhbazov K, Barbier V, Krishnan K, Mukhopadhyay P, et al. Interaction of c-Myb with p300 is required for the induction of acute myeloid leukemia (AML) by human AML oncogenes. Blood. 2014;123:2682–90. [DOI] [PubMed]

30.

Liu X, Xu Y, Han L, Yi Y. Reassessing the potential of Myb-targeted anti-cancer therapy. J Cancer. 2018;9:1259–66. [DOI] [PubMed] [PMC]

31.

Uttarkar S, Piontek T, Dukare S, Schomburg C, Schlenke P, Berdel WE, et al. Small-molecule disruption of the Myb/p300 cooperation targets acute myeloid leukemia cells. Mol Cancer Ther. 2016;15:2905–15. [DOI] [PubMed]

32.

Thomas LR, Adams CM, Wang J, Weissmiller AM, Creighton J, Lorey SL, et al. Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance. Proc Natl Acad Sci U S A. 2019;116:25260–8. [DOI] [PubMed] [PMC]

33.

Fletcher S, Turkson J, Gunning PT. Molecular approaches towards the inhibition of the signal transducer and activator of transcription 3 (Stat3) protein. ChemMedChem. 2008;3:1159–68. [DOI] [PubMed] [PMC]

34.

Mandal PK, Ren Z, Chen X, Xiong C, McMurray JS. Structure-affinity relationships of glutamine mimics incorporated into phosphopeptides targeted to the SH2 domain of signal transducer and activator of transcription 3. J Med Chem. 2009;52:6126–41. [DOI] [PubMed] [PMC]

35.

Mandal PK, Liao WS, McMurray JS. Synthesis of phosphatase-stable, cell-permeable peptidomimetic prodrugs that target the SH2 domain of Stat3. Org Lett. 2009;11:3394–7. [DOI] [PubMed] [PMC]

36.

Mandal PK, Limbrick D, Coleman DR, Dyer GA, Ren Z, Birtwistle JS, et al. Conformationally constrained peptidomimetic inhibitors of signal transducer and activator of transcription 3: evaluation and molecular modeling. J Med Chem. 2009;52:2429–42. [DOI] [PubMed] [PMC]

37.

Miranda E, Nordgren IK, Male AL, Lawrence CE, Hoakwie F, Cuda F, et al. A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells. J Am Chem Soc. 2013;135:10418–25. [DOI] [PubMed] [PMC]

38.

Kribelbauer JF, Rastogi C, Bussemaker HJ, Mann RS. Low-affinity binding sites and the transcription factor specificity paradox in eukaryotes. Annu Rev Cell Dev Biol. 2019;35:357–79. [DOI] [PubMed] [PMC]

39.

Walf-Vorderwülbecke V, Pearce K, Brooks T, Hubank M, van den Heuvel-Eibrink MM, Zwaan CM, et al. Targeting acute myeloid leukemia by drug-induced c-MYB degradation. Leukemia. 2018;32:882–9. [DOI] [PubMed]

40.

Naito M, Ohoka N, Shibata N, Tsukumo Y. Targeted protein degradation by chimeric small molecules, PROTACs and SNIPERs. Front Chem. 2019;7:849. [DOI] [PubMed] [PMC]

41.

Tewari D, Nabavi SF, Nabavi SM, Sureda A, Farooqi AA, Atanasov AG, et al. Targeting activator protein 1 signaling pathway by bioactive natural agents: possible therapeutic strategy for cancer prevention and intervention. Pharmacol Res. 2018;128:366–75. [DOI] [PubMed]

42.

Loh CY, Arya A, Naema AF, Wong WF, Sethi G, Looi CY. Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol. 2019;9:48. [DOI] [PubMed] [PMC]

43.

Kashyap D, Tuli HS, Yerer MB, Sharma A, Sak K, Srivastava S, et al. Natural product-based nanoformulations for cancer therapy: opportunities and challenges. Semin Cancer Biol. 2019;[Epub ahead of print]. [DOI]

44.

Kim C, Cho SK, Kapoor S, Kumar A, Vali S, Abbasi T, et al. beta-Caryophyllene oxide inhibits constitutive and inducible STAT3 signaling pathway through induction of the SHP-1 protein tyrosine phosphatase. Mol Carcinog. 2014;53:793–806. [DOI] [PubMed]

45.

Lee JH, Kim C, Sethi G, Ahn KS. Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel. Oncotarget. 2015;6:6386–405. [DOI] [PubMed] [PMC]