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Twist family bHLH transcription factor 2 (TWIST2)
- Target
- TWIST2
- Molecular classification
- Transcription factor, Basic helix-loop-helix (bHLH) protein, DNA-binding protein
01
Overview
Twist family bHLH transcription factor 2 (TWIST2) is a DNA-binding transcription factor of the basic helix-loop-helix (bHLH) family, closely related to TWIST1, and expressed tissue-specifically. TWIST2 heterodimerizes with other bHLH factors to regulate cell lineage determination, mesoderm induction, and differentiation. In osteogenesis, TWIST2 maintains cells in a preosteoblast state by inhibiting differentiation; it also represses pro-inflammatory cytokine expression. In cancer, TWIST2 promotes epithelial-mesenchymal transition (EMT), metastasis, chemotherapy resistance, and is associated with poor prognosis. Mutations in TWIST2 cause several congenital craniofacial syndromes. Currently, TWIST2 is a validated preclinical therapeutic target for EMT and metastasis, but as a transcription factor, it presents challenges for direct drug targeting
- Other names
- Twist-related protein 2BHLHA39DERMO1dermis-expressed protein 1bHLHa39Dermo-1AMSBBRSAYFFDD3SETLSSclass A basic helix-loop-helix protein 39twist basic helix-loop-helix transcription factor 2twist homolog 2twist-related bHLH protein Dermo1
02
Mechanism of action
Not established for approved drugs. Mechanistically, inhibition of TWIST2 or its protein-protein interaction complexes (with NuRD/Mi2, HDAC2, MTA2, etc.) could theoretically reverse EMT or reduce metastasis
03
Biological functions
DNA bindingProtein binding and dimerization (forms homo- and heterodimers with other bHLH proteins, such as E12, E47, TWIST1)Inhibition of osteoblast maturation (maintains preosteoblast phenotype)Regulation of mesoderm induction and cell lineage determinationRepression of pro-inflammatory cytokine expression (e.g., TNFA, IL1B)Regulation of epithelial-mesenchymal transition (EMT)Repression of E-cadherin and β-catenin expressionModulation of cell motility, invasiveness, and metastasis
04
Disease associations
Cancer (multiple types, notably breast, hepatocellular, prostate, gastric, bladder; role in EMT, metastasis, therapy resistance)Ablepharon-macrostomia syndrome (genetic disorder)Barber–Say syndrome (genetic disorder)Focal facial dermal dysplasia type 3 (Setleis type)
05
Safety considerations
TWIST2 plays roles in development and normal tissue differentiation; systemic inhibition may risk developmental defects or interfere with tissue homeostasis.Targeting broadly acting transcription factors often poses safety/efficacy challenges because of their central role in regulating multiple genesMutations can cause congenital syndromes; thus, modulation must be approached cautiously
06
Interacting drugs
No approved drugs are directly listed as targeting TWIST2. Experimental targeting of TWIST2 and its pathway is being investigated in preclinical cancer models
07
Biomarkers
Overexpression or high activity of TWIST2 may serve as a biomarker for EMT-associated cancer aggressiveness, poor prognosis, and resistance to therapies such as TaxolMutation in TWIST2 is a diagnostic biomarker for certain syndromic craniofacial disorders (e.g., ablepharon-macrostomia, Barber–Say)
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