title: The twist box domain is required for Twist1-induced prostate cancer metastasis.
abstract: Twist1, a basic helix-loop-helix transcription factor, plays a key role during development and is a master regulator of the epithelial-mesenchymal transition (EMT) that promotes cancer metastasis. Structure-function relationships of Twist1 to cancer-related phenotypes are underappreciated, so we studied the requirement of the conserved Twist box domain for metastatic phenotypes in prostate cancer. Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in prostate cancer cells using in vitro assays, which mimic various stages of metastasis. Twist1 overexpression led to elevated cytoskeletal stiffness and cell traction forces at the migratory edge of cells based on biophysical single-cell measurements. Twist1 conferred additional cellular properties associated with cancer cell metastasis including increased migration, invasion, anoikis resistance, and anchorage-independent growth. The Twist box mutant was defective for these Twist1 phenotypes in vitro. Importantly, we observed a high frequency of Twist1-induced metastatic lung tumors and extrathoracic metastases in vivo using the experimental lung metastasis assay. The Twist box was required for prostate cancer cells to colonize metastatic lung lesions and extrathoracic metastases. Comparative genomic profiling revealed transcriptional programs directed by the Twist box that were associated with cancer progression, such as Hoxa9. Mechanistically, Twist1 bound to the Hoxa9 promoter and positively regulated Hoxa9 expression in prostate cancer cells. Finally, Hoxa9 was important for Twist1-induced cellular phenotypes associated with metastasis. These data suggest that the Twist box domain is required for Twist1 transcriptional programs and prostate cancer metastasis.
  
  
  CONCLUSIONS
  Targeting the Twist box domain of Twist1 may effectively limit prostate cancer metastatic potential.
authors: Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, 1550 Orleans Street, CRB2 Rm 406, Baltimore, MD 21231. tranp@jhmi.edu.
authors: Rajendra P
authors: RP
authors: Gajula
authors: Sivarajan T
authors: ST
authors: Chettiar
authors: Russell D
authors: RD
authors: Williams
authors: Saravanan
authors: S
authors: Thiyagarajan
authors: Yoshinori
authors: Y
authors: Kato
authors: Khaled
authors: K
authors: Aziz
authors: Ruoqi
authors: R
authors: Wang
authors: Nishant
authors: N
authors: Gandhi
authors: Aaron T
authors: AT
authors: Wild
authors: Farhad
authors: F
authors: Vesuna
authors: Jinfang
authors: J
authors: Ma
authors: Tarek
authors: T
authors: Salih
authors: Jessica
authors: J
authors: Cades
authors: Elana
authors: E
authors: Fertig
authors: Shyam
authors: S
authors: Biswal
authors: Timothy F
authors: TF
authors: Burns
authors: Christine H
authors: CH
authors: Chung
authors: Charles M
authors: CM
authors: Rudin
authors: Joseph M
authors: JM
authors: Herman
authors: Russell K
authors: RK
authors: Hales
authors: Venu
authors: V
authors: Raman
authors: Steven S
authors: SS
authors: An
authors: Phuoc T
authors: PT
authors: Tran
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics*; D015533:Transcriptional Activation; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C097899:homeobox protein HOXA9
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