The epigenetic factor KDM2B regulates cell adhesion, small rho GTPases, actin cytoskeleton and migration in prostate cancer cells

TY - JOUR

T1 - The epigenetic factor KDM2B regulates cell adhesion, small rho GTPases, actin cytoskeleton and migration in prostate cancer cells

AU - Zacharopoulou, Nefeli

AU - Tsapara, Anna

AU - Kallergi, Galatea

AU - Schmid, Evi

AU - Tsichlis, Philip N

AU - Kampranis, Sotirios C

AU - Stournaras, Christos

N1 - Copyright © 2018 Elsevier B.V. All rights reserved.

PY - 2018/4

Y1 - 2018/4

N2 - The histone demethylase KDM2B is an epigenetic factor with oncogenic properties that is regulated by the basic fibroblasts growth factor (FGF-2). It has recently been shown that KDM2B co-operates with Polycomb Group proteins to promote cell migration and angiogenesis in tumors. In the present study we addressed the role of KDM2B in regulating actin cytoskeleton signaling, cell-cell adhesion and migration of prostate tumor cells. We report here that KDM2B is functionally expressed in DU-145 prostate cancer cells, activated by FGF-2 and regulates EZH2. KDM2B knockdown induced potent up-regulation of gene transcription and protein expression of the epithelial markers E-cadherin and ZO-1, while KDM2B overexpression down-regulated the levels of both markers, suggesting control of cell adhesion by KDM2B. RhoA and RhoB protein expression and activity were diminished upon KDM2B-knockdown and upregulated in KDM2B-overexpressing cell clones. In accordance, actin reorganization with formation of stress fibers became evident in KDM2B-overexpressing cells and abolished in the presence of the Rho inhibitor C3 transferase. DU-145 cell migration was significantly enhanced in KDM2B overexpressing cells and abolished in C3-pretreated cells. Conversely, the retardation of cell migration observed in KDM2B knockdown cells was enhanced in C3-pretreated cells. These results establish a clear functional link between the epigenetic factor KDM2B and the regulation of cell adhesion and Rho-GTPases signaling that controls actin reorganization and cell migration.

AB - The histone demethylase KDM2B is an epigenetic factor with oncogenic properties that is regulated by the basic fibroblasts growth factor (FGF-2). It has recently been shown that KDM2B co-operates with Polycomb Group proteins to promote cell migration and angiogenesis in tumors. In the present study we addressed the role of KDM2B in regulating actin cytoskeleton signaling, cell-cell adhesion and migration of prostate tumor cells. We report here that KDM2B is functionally expressed in DU-145 prostate cancer cells, activated by FGF-2 and regulates EZH2. KDM2B knockdown induced potent up-regulation of gene transcription and protein expression of the epithelial markers E-cadherin and ZO-1, while KDM2B overexpression down-regulated the levels of both markers, suggesting control of cell adhesion by KDM2B. RhoA and RhoB protein expression and activity were diminished upon KDM2B-knockdown and upregulated in KDM2B-overexpressing cell clones. In accordance, actin reorganization with formation of stress fibers became evident in KDM2B-overexpressing cells and abolished in the presence of the Rho inhibitor C3 transferase. DU-145 cell migration was significantly enhanced in KDM2B overexpressing cells and abolished in C3-pretreated cells. Conversely, the retardation of cell migration observed in KDM2B knockdown cells was enhanced in C3-pretreated cells. These results establish a clear functional link between the epigenetic factor KDM2B and the regulation of cell adhesion and Rho-GTPases signaling that controls actin reorganization and cell migration.

KW - Actin Cytoskeleton/metabolism

KW - Biomarkers, Tumor/metabolism

KW - Cadherins/metabolism

KW - Cell Adhesion/genetics

KW - Cell Line, Tumor

KW - Cell Movement/genetics

KW - Enhancer of Zeste Homolog 2 Protein/metabolism

KW - Epigenesis, Genetic

KW - F-Box Proteins/genetics

KW - Gene Expression Regulation, Neoplastic

KW - HEK293 Cells

KW - Humans

KW - Jumonji Domain-Containing Histone Demethylases/genetics

KW - Male

KW - Models, Biological

KW - Prostatic Neoplasms/genetics

KW - Zonula Occludens-1 Protein/metabolism

KW - rho GTP-Binding Proteins/metabolism

U2 - 10.1016/j.bbamcr.2018.01.009

DO - 10.1016/j.bbamcr.2018.01.009

M3 - Journal article

C2 - 29408056

SN - 0167-4889

VL - 1865

SP - 587

EP - 597

JO - B B A - Molecular Cell Research

JF - B B A - Molecular Cell Research

IS - 4

ER -