The Twist Box Domain is Required for Twist1-induced Prostate Cancer Metastasis

Rajendra P Gajula; Sivarajan T Chettiar; Russell D Williams; Saravanan Thiyagarajan; Yoshinori Kato; Khaled Aziz; Ruoqi Wang; Nishant Gandhi; Aaron T Wild; Farhad Vesuna; Jinfang Ma; Tarek Salih; Jessica Cades; Elana Fertig; Shyam Biswal; Timothy F Burns; Christine H Chung; Charles M Rudin; Joseph M Herman; Russell K Hales; Venu Raman; Steven S An; Phuoc T Tran

doi:10.1158/1541-7786.MCR-13-0218-T

Back

The Twist Box Domain is Required for Twist1-induced Prostate Cancer Metastasis

Journal article

Open access

Peer reviewed

The Twist Box Domain is Required for Twist1-induced Prostate Cancer Metastasis

Rajendra P Gajula, Sivarajan T Chettiar, Russell D Williams, Saravanan Thiyagarajan, Yoshinori Kato, Khaled Aziz, Ruoqi Wang, Nishant Gandhi, Aaron T Wild, Farhad Vesuna, …

Molecular cancer research, Vol.11(11), pp.1387-1400

11/2013

DOI: https://doi.org/10.1158/1541-7786.MCR-13-0218-T

PMCID: PMC3833995

PMID: 23982216

Abstract

prostate cancer

epithelial-mesenchymal transition

Hoxa9

Twist box

metastasis

Twist1

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 (PCa). Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in PCa 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 extra-thoracic metastases in vivo using the experimental lung metastasis assay. The Twist box was required for PCa cells to colonize metastatic lung lesions and extra-thoracic 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 PCa 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 PCa metastasis.

Files and links (1)

url

https://doi.org/10.1158/1541-7786.MCR-13-0218-TView

Version of Record (VoR) Open

Metrics

8 Record Views

57 Times Cited - Web of Science

See more details

Details

Title: The Twist Box Domain is Required for Twist1-induced Prostate Cancer Metastasis
Creators: Rajendra P Gajula - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Sivarajan T Chettiar - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Russell D Williams - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Saravanan Thiyagarajan - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Yoshinori Kato - The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Khaled Aziz - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Ruoqi Wang - Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
Nishant Gandhi - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Aaron T Wild - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Farhad Vesuna - The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jinfang Ma - Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
Tarek Salih - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jessica Cades - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Elana Fertig - Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Shyam Biswal - Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
Timothy F Burns - Department of Medicine, Division of Hematology-Oncology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
Christine H Chung - Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Charles M Rudin - Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Joseph M Herman - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Russell K Hales - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Venu Raman - The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Steven S An - Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
Phuoc T Tran - Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Publication Details: Molecular cancer research, Vol.11(11), pp.1387-1400
Date published: 11/2013
Grant note: P50 CA103175 || CA / National Cancer Institute : NCI R01 CA166348 || CA / National Cancer Institute : NCI
Academic Unit: Clinical and Translational Research
Language: English
Resource Type: Journal article
Identifiers: 991031654717504646