4.3 Article

Structure-Function Studies of the bHLH Phosphorylation Domain of TWIST1 in Prostate Cancer Cells

Journal

NEOPLASIA
Volume 17, Issue 1, Pages 16-31

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2014.10.009

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Funding

  1. National Institutes of Health (NIH) [1R0AR061392]
  2. NIH [P50CA103175, U54CA141868, HL107361, R01CA166348]
  3. Irene and Bernard L. Schwartz Scholar Award from the Patrick C. Walsh Prostate Cancer Research Fund
  4. Department of Defense (DoD) [W81XWH-11-1-0272, W81XWH-13-1-0182]
  5. Kimmel Translational Science Award [SKF-13-021]
  6. ACS Scholar Award [122688-RSG-12-196-01-TBG]

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The TWIST1 gene has diverse roles in development and pathologic diseases such as cancer. TWIST1 is a dimeric basic helix-loop-helix (bHLH) transcription factor existing as TWIST1-TWIST1 or TWIST1-E12/47. TWIST1 partner choice and DNA binding can be influenced during development by phosphorylation of Thr125 and Ser127 of the Thr-Gln-Ser (TQS) motif within the bHLH of TWIST1. The significance of these TWIST1 phosphorylation sites for metastasis is unknown. We created stable isogenic prostate cancer cell lines overexpressing TWIST1 wild-type, phospho-mutants, and tethered versions. We assessed these isogenic lines using assays that mimic stages of cancer metastasis. In vitro assays suggested the phospho-mimetic Twist1-DQD mutation could confer cellular properties associated with pro-metastatic behavior. The hypo-phosphorylation mimic Twist1-AQA mutation displayed reduced pro-metastatic activity compared to wild-type TWIST1 in vitro, suggesting that phosphorylation of the TWIST1 TQS motif was necessary for pro-metastatic functions. In vivo analysis demonstrates that the Twist1-AQA mutation exhibits reduced capacity to contribute to metastasis, whereas the expression of the Twist1-DQD mutation exhibits proficient metastatic potential. Tethered TWIST1-E12 heterodimers phenocopied the Twist1-DQD mutation for many in vitro assays, suggesting that TWIST1 phosphorylation may result in heterodimerization in prostate cancer cells. Lastly, the dual phosphatidylinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor BEZ235 strongly attenuated TWIST1-induced migration that was dependent on the TQS motif. TWIST1 TQS phosphorylation state determines the intensity of TWIST1-induced pro-metastatic ability in prostate cancer cells, which may be partly explained mechanistically by TWIST1 dimeric partner choice.

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