A mini-review of the molecular mechanisms, mutational landscape, and therapeutic opportunities of TWIST1 in oncology.

TWIST1 is a deeply conserved basic helix-loop-helix (bHLH) transcription factor that has emerged as a central transcriptional regulator bridging developmental biology and cancer pathogenesis. This key regulator orchestrates mesoderm formation, neural crest migration, and craniofacial morphogenesis through precise dimerization-dependent mechanisms. The TWIST1 bHLH domain mediates DNA binding at E-box motifs (CANNTG), with its regulatory role determined by homodimer versus E-protein heterodimer formation. Recent reports demonstrate that post-translational modifications (PTMs) are critical for TWIST1 activity: diacetylation at K73/K76 by TIP60 recruits BRD8 to activate mesenchymal and MYC targets, whereas non-acetylated TWIST1 recruits the NuRD repressor complex to silence epithelial genes. Aurora kinase A (AURKA) phosphorylation at three sites stabilizes TWIST1, promotes homodimerization, and drives chemoresistance, while SETD6-mediated K33 methylation enhances EZH2 occupancy and H3K27me3 deposition at the LINC-PINT locus. Germline loss-of-function mutations clustered in the bHLH domain cause Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis disorder characterized by protein degradation or impaired nuclear localization. Therapeutic targeting TWIST1 remains challenging due to the absence of deep binding pockets, but emerging strategies include harmine (a β-carboline alkaloid)-mediated proteasomal degradation, BRD4/TIP60/BRD8 axis inhibition, and transcription factor-targeted proteolysis-targeting chimeras (TF-PROTACs) employing DNA oligonucleotide warheads linked to E3 ligase ligands. This review summarizes classic and recent findings on structural biology, PTM networks, mutation landscapes, oncogenic mechanisms, and therapeutic frontiers, highlighting TWIST1 as a target for precision oncology and therapy.