Tumour-suppression function of KLF12 through regulation of anoikis.

N Godin-Heymann,M M Murillo,N Matthews,S Brabetz,E Castellano,G Kelly,S Jordan,A Lobley,C R Santos,P East,P Chakravarty,M Saponaro,J Downward

doi:10.1038/onc.2015.394

Abstract

Suppression of detachment-induced cell death, known as anoikis, is an essential step for cancer metastasis to occur. We report here that expression of KLF12, a member of the Kruppel-like family of transcription factors, is downregulated in lung cancer cell lines that have been selected to grow in the absence of cell adhesion. Knockdown of KLF12 in parental cells results in decreased apoptosis following cell detachment from matrix. KLF12 regulates anoikis by promoting the cell cycle transition through S phase and therefore cell proliferation. Reduced expression levels of KLF12 results in increased ability of lung cancer cells to form tumours in vivo and is associated with poorer survival in lung cancer patients. We therefore identify KLF12 as a novel metastasis-suppressor gene whose loss of function is associated with anoikis resistance through control of the cell cycle.

Highlights

Metastasis is a multi-step process involving tumour cells leaving their site of origin, spreading via blood or lymph vessels and forming new tumours at distant sites
The apoptotic population of A549 PAR cells grown on polyHEMA was significantly reduced in cells in which KLF12 was knocked down by short hairpin RNA (shRNA) (Figure 3b)
Aphidicolin plastic passage shSCR shKLF12 population doublings relative apoptosis pHEMA/plastic able to significantly reduce the apoptotic population of cells grown on polyHEMA compared with those treated with a dimethyl sulphoxide control (Figure 5c)

Summary

Introduction

Metastasis is a multi-step process involving tumour cells leaving their site of origin, spreading via blood or lymph vessels and forming new tumours at distant sites. The effect of the extracellular matrix (ECM) on cells is mainly mediated by integrins, a family of transmembrane receptors that bind to the ECM and transduce intracellular signalling pathways. Upon integrin-mediated adhesion, both FAK and SRC are activated and they in turn activate various pathways such as phosphatidylinositol 3′-kinase/AKT, RAS/RAF/MEK/extracellular signal–regulated kinase (ERK) and nuclear factor-κB, resulting in overall survival signals.[1,2] when the integrin signal is lost due to cell detachment, these survival pathways are no longer dominant and anoikis occurs. Metastatic cells have developed various mechanisms to overcome anoikis, including epithelial-tomesenchymal transition, changes in integrin repertoire, integrin internalization, constitutive activation of pro-survival signals such as autocrine secretion of growth factors or receptor tyrosine kinase overexpression, oxidative stress, autophagy or entosis.[3,4]

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