Table 1.

Transcription factor PTMs as therapeutic targets

PTM affected	Target Protein	Potential Use	Comments	Refs
Phosphorylation	Tyrosine kinases	Treatment of cancer, rheumatoid arthritis,	Inhibition of tyrosine kinases by drugs, such as imatinib, ruxolitinib, and tofactinib, directly inhibits phosphorylation of STAT proteins, and indirectly inhibits phosphorylation of other transcription factors, including c-JUN, Rb1, Tp73, YAP1, and β-catenin.	[72]
	Cyclin-dependent kinase 5 (CDK5)	Type 2 diabetes mellitus	Inhibition of CDK5-mediated phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) may be useful for T2DM.	[73]
	Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (PIN1)	Treatment of cancer, including cancer of the breast	PIN1 isomerizes the pSer118–Pro119 bond of estrogen receptor α (ERα), increasing ligand-independent transcriptional activation mediated by ERα and inhibiting proteosomal-dependent degradation of the phospho-activated receptor. PIN1 expression is also elevated in some breast cancers that exhibit poor outcomes and numerous PIN1 inhibitors are in development.	[52,74–76]
	Calcineurin (protein phosphatase 3)	Immunosuppressant	Calcineurin activity is required to dephosphorylate and promote translocation of the transcription factor NFAT from the cytosol to the nucleus. Inhibition of calcineurin by FK506 (tacrolimus) prevents nuclear translocation of NFAT in T lymphocytes, leading to reduced expression of IL-2 and suppression of adaptive immunity.	[11]
	SMAD phosphatases	Spinal cord injury	Phosphorylated members of the SMAD family of transcription factors promote motor neuron axonal outgrowth. Inhibition of SMAD phosphatases may prolong the active lifetime of phospho-SMAD proteins.	[77,78]
Sumoylation	PML-RARα	Acute promyelocytic leukemia	Arsenic Trioxide (As2O3) promotes oligomerization and sumoylation of the PML portion of the PML- RARα fusion protein, with subsequent ubiquitination of the protein via SUMO-targeted ubiquitin ligases (STUbL proteins) and proteosomal degradation.	[71]
	SENP proteins	Treatment of cancer	Inhibition of SENP proteins by betulinic acid and related compounds may prolong the lifetime of sumoylated transcription factors, such as SP1.	[79,80]
Ubiquitination	p53	Treatment of cancer	Compounds such as Nutlin-3 bind to the MDM2 binding pocket of p53, inhibiting p53-MDM2 interaction and MDM2-mediated ubiquitination of p53, and prolonging the lifetime of activated p53.	[81]
Methylation	Co-activator-associated arginine methyltransferase 1 (CARM1)	Treatment of cancer, potentially other disorders	Indole and/or pyazole inhibitors of the catalytic function of CARM1 may interrupt signaling by estrogen receptors in breast cancer, or other transcription factors in other hormone-dependent tumors.	[82,83]
O-GlcNAcylation	O-GlcNAc transferase (OGT)	Treatment of cancer; particularly of the breast	Inhibition of OGT may sensitize breast cancer cells to tamoxifen therapy.	[84]
	O-GlcNAc hydrolase (O-GlcNAcase)	As yet unknown	Inhibition of O-GlcNAcase by compounds, such as Thiamet-G, may be a means of altering the O- GlcNAc/phosphorylation reciprocal balance toward O-GlcNAc. This may serve to turn off transcription factors that require phosphorylation for activity. A similar observation has been made in the case of Tau kinases, which become hyperphosphorylated in Alzheimer’s disease and drive tau-mediated neurodegeneration.	[85,86]
Acetylation	Histone acetyltransferases (HATs)	Treatment of cancer, HIV	Garcinol, a natural compound, inhibits HAT activity of p300/CBP and may be useful to reprogram histone and transcription factor modifications that are characteristic of disease processes, such as cancer and HIV.	[87,88]