RAC1 activation mediates Twist1-induced cancer cell migration

Wen Hao Yang; Hsin Yi Lan; Chi Hung Huang; Shyh Kuan Tai; Cheng Hwai Tzeng; Shou Yen Kao; Kou Juey Wu; Mien Chie Hung; Muh Hwa Yang

doi:10.1038/ncb2455

RAC1 activation mediates Twist1-induced cancer cell migration

Wen Hao Yang
, Hsin Yi Lan
, Chi Hung Huang
, Shyh Kuan Tai
, Cheng Hwai Tzeng
, Shou Yen Kao
, Kou Juey Wu
, Mien Chie Hung
, Muh Hwa Yang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

207 Scopus citations

Abstract

Epithelial-mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1-let-7i-NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin.

Original language	English
Pages (from-to)	366-374
Number of pages	9
Journal	Nature Cell Biology
Volume	14
Issue number	4
DOIs	https://doi.org/10.1038/ncb2455
State	Published - Apr 2012

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@article{9b862c0ebf82480392aa4e2e4c4dfdb3,

title = "RAC1 activation mediates Twist1-induced cancer cell migration",

abstract = "Epithelial-mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1-let-7i-NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin.",

author = "Yang, \{Wen Hao\} and Lan, \{Hsin Yi\} and Huang, \{Chi Hung\} and Tai, \{Shyh Kuan\} and Tzeng, \{Cheng Hwai\} and Kao, \{Shou Yen\} and Wu, \{Kou Juey\} and Hung, \{Mien Chie\} and Yang, \{Muh Hwa\}",

note = "Funding Information: We thank M. F. Olson (The Beaston Institute for Cancer Research, UK) for providing the ROCK–ER-WT and ROCK–ER-K121G plasmids, and H. Kimura (National Institute of Neuroscience, Tokyo, Japan) for the pCl–neo–DOCK3HA plasmid. We thank T. Z. Huang, Y. B. Khotskaya, C. W. Lee and S. S. Chang (M. D. Anderson Cancer Center, Texas, USA) for critical comments on the manuscript. We thank C. H. Lin and H. W. Liu (National Yang-Ming University, Taiwan) for supporting the time-lapse microscopy techniques. This work was supported by the National Health Research Institutes (NHRI-EX100-10037BI to M-H.Y.; NHRI-EX100-9931BI to K-J.W.); the National Science Council (NSC 99-2314-B-010-007-MY3 and 100-2321-B-010-015 to M-H.Y.; NSC 100-2321-B-039-002 to M-C.H.); Taipei Veterans General Hospital (VGH 100-C-088, 101-C-005 to M-H.Y.); Veterans General Hospitals University System of Taiwan Joint Research Program (VGHUST101-G7-4-1 to M-H.Y.); a grant from the Ministry of Education, Aim for the Top University Plan (to M-H.Y.); a grant from the Department of Health, Center of Excellence for Cancer Research (DOH100-TD-C-111-007 to M-H.Y; DOH101-TD-C-111-005 to M-C.H.); and the Sister Institution Fund of China Medical University and Hospital and MD Anderson Cancer Center.",

year = "2012",

month = apr,

doi = "10.1038/ncb2455",

language = "English",

volume = "14",

pages = "366--374",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

number = "4",

}

TY - JOUR

T1 - RAC1 activation mediates Twist1-induced cancer cell migration

AU - Yang, Wen Hao

AU - Lan, Hsin Yi

AU - Huang, Chi Hung

AU - Tai, Shyh Kuan

AU - Tzeng, Cheng Hwai

AU - Kao, Shou Yen

AU - Wu, Kou Juey

AU - Hung, Mien Chie

AU - Yang, Muh Hwa

N1 - Funding Information: We thank M. F. Olson (The Beaston Institute for Cancer Research, UK) for providing the ROCK–ER-WT and ROCK–ER-K121G plasmids, and H. Kimura (National Institute of Neuroscience, Tokyo, Japan) for the pCl–neo–DOCK3HA plasmid. We thank T. Z. Huang, Y. B. Khotskaya, C. W. Lee and S. S. Chang (M. D. Anderson Cancer Center, Texas, USA) for critical comments on the manuscript. We thank C. H. Lin and H. W. Liu (National Yang-Ming University, Taiwan) for supporting the time-lapse microscopy techniques. This work was supported by the National Health Research Institutes (NHRI-EX100-10037BI to M-H.Y.; NHRI-EX100-9931BI to K-J.W.); the National Science Council (NSC 99-2314-B-010-007-MY3 and 100-2321-B-010-015 to M-H.Y.; NSC 100-2321-B-039-002 to M-C.H.); Taipei Veterans General Hospital (VGH 100-C-088, 101-C-005 to M-H.Y.); Veterans General Hospitals University System of Taiwan Joint Research Program (VGHUST101-G7-4-1 to M-H.Y.); a grant from the Ministry of Education, Aim for the Top University Plan (to M-H.Y.); a grant from the Department of Health, Center of Excellence for Cancer Research (DOH100-TD-C-111-007 to M-H.Y; DOH101-TD-C-111-005 to M-C.H.); and the Sister Institution Fund of China Medical University and Hospital and MD Anderson Cancer Center.

PY - 2012/4

Y1 - 2012/4

N2 - Epithelial-mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1-let-7i-NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin.

AB - Epithelial-mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1-let-7i-NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin.

UR - https://www.scopus.com/pages/publications/84862777514

U2 - 10.1038/ncb2455

DO - 10.1038/ncb2455

M3 - Article

C2 - 22407364

AN - SCOPUS:84862777514

SN - 1465-7392

VL - 14

SP - 366

EP - 374

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

ER -

RAC1 activation mediates Twist1-induced cancer cell migration

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