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Open Access Research article

TWIST1 associates with NF-κB subunit RELA via carboxyl-terminal WR domain to promote cell autonomous invasion through IL8 production

Shan Li14, Stephen E Kendall16, Raquel Raices110, James Finlay14, Maricela Covarrubias17, Zheng Liu3, Gina Lowe1, Yu-Huey Lin15, Yuan Han Teh15, Victoria Leigh18, Simi Dhillon19, Steven Flanagan1, Karen S Aboody12 and Carlotta A Glackin1*

Author Affiliations

1 Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA

2 Department of Neurosurgery, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA

3 Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA

4 Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA

5 Department of Biological Sciences, California State Polytechnic Institute, Pomona, CA 91768, USA

6 GeneTex, Irvine, CA 92606, USA

7 Affymetrix, Santa Clara, CA 95051, USA

8 Western University of Health Sciences, Pomona, CA 91766, USA

9 University of California Berkeley, Berkeley, CA 94720, USA

10 StemCell Technologies Inc., Vancouver, BC V5Z 1B3, Canada

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BMC Biology 2012, 10:73  doi:10.1186/1741-7007-10-73

Published: 14 August 2012

Abstract

Background

Metastasis is the primary cause of death for cancer patients. TWIST1, an evolutionarily conserved basic helix-loop-helix (bHLH) transcription factor, is a strong promoter of metastatic spread and its expression is elevated in many advanced human carcinomas. However, the molecular events triggered by TWIST1 to motivate dissemination of cancer cells are largely unknown.

Results

Here we show that TWIST1 induces the production of interleukin 8 (IL8), which activates matrix metalloproteinases and promotes invasion of breast epithelial and cancer cells. In this novel mechanism, TWIST1-mediated IL8 transcription is induced through the TWIST1 carboxy-terminal WR (Trp-Arg) domain instead of the classic DNA binding bHLH domain. Co-immunoprecipitation analyses revealed that the WR domain mediates the formation of a protein complex comprised of TWIST1 and the nuclear factor-kappaB (NF-κB) subunit RELA (p65/NF-κB3), which synergistically activates the transcriptional activity of NF-κB. This activation leads to increased DNA binding affinity of RELA to the IL8 promoter and thus induces the expression of the cytokine. Blockage of IL8 signaling by IL8 neutralizing antibodies or receptor inhibition reduced the invasiveness of both breast epithelial and cancer cells, indicating that TWIST1 induces autonomous cell invasion by establishing an IL8 antocrine loop.

Conclusions

Our data demonstrate that the TWIST1 WR domain plays a critical role in TWIST1-induced IL8 expression through interactions with and activation of NF-κB. The produced IL8 signals through an autocrine loop and promotes extracellular matrix degradation to enable cell invasion across the basement membrane.

Keywords:
TWIST1; WR domain; RELA; NF-κB; IL8