Amatangelo M.

Conejo-Garcia J.

Garipov A.

Li H.

Speicher D.

Zhang R.

Cell Cycle

Gallica, Bibliotheque Numerique

La Patrie : journal quotidien, politique, commercial et littéraire

Inhibitors of EZH2 methyltransferase activity have been demonstrated to selectively suppress the growth of diffused large B cell lymphoma (DLBCL) cells with gain-of-function mutations in EZH2, while exhibiting very limited effects on the growth of DLBCL cells with wild-type EZH2. Given that EZH2 is often overexpressed but not mutated in solid tumors, it is important to investigate the determinants of sensitivity of solid tumor cells to EZH2 inhibitors. In the current study, we show that three-dimensional (3D) culture of epithelial ovarian cancer (EOC) cells that overexpress EZH2 sensitizes these cells to EZH2 methyltransferase inhibition. Treatment of EOC cells with GSK343, a specific inhibitor of EZH2 methyltransferase, decreases the level of H3K27Me3, the product of EZH2's enzymatic activity. However, GSK343 exhibited limited effects on the growth of EOC cells in conventional two-dimensional (2D) culture. In contrast, GSK343 significantly suppressed the growth of EOC cells cultured in 3D matrigel extracellular matrix (ECM), which more closely mimics the tumor microenvironment in vivo. Notably, GSK343 induces apoptosis of EOC cells in 3D but not 2D culture. In addition, GSK343 significantly inhibited the invasion of EOC cells. In summary, we show that the 3D ECM sensitizes EOC cells to EZH2 methyltransferase inhibition, which suppresses cell growth, induces apoptosis and inhibits invasion. Our findings imply that in EZH2 wild-type solid tumors, the ECM tumor microenvironment plays an important role in determining sensitivity to EZH2 inhibition and suggest that targeting the ECM represents a novel strategy for enhancing EZH2 inhibitor efficacy. © 2013 Landes Bioscience

Kazan Federal University Digital Repository

Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition

Cell Cycle 2013 vol.12 N13, pages 2113-2119Three-dimensional culture sensitizes epithelial ovariancancer cells to EZH2 methyltransferase inhibitionAmatangelo M., Garipov A., Li H., Conejo-Garcia J., Speicher D., Zhang R.Kazan Federal University, 420008, Kremlevskaya 18, Kazan, RussiaAbstractInhibitors of EZH2 methyltransferase activity have been demonstrated to selectively suppressthe growth of diffused large B cell lymphoma (DLBCL) cells with gain-of-function mutations inEZH2, while exhibiting very limited effects on the growth of DLBCL cells with wild-type EZH2.Given that EZH2 is often overexpressed but not mutated in solid tumors, it is important toinvestigate the determinants of sensitivity of solid tumor cells to EZH2 inhibitors. In the currentstudy, we show that three-dimensional (3D) culture of epithelial ovarian cancer (EOC) cells thatoverexpress EZH2 sensitizes these cells to EZH2 methyltransferase inhibition. Treatment of EOCcells  with  GSK343,  a  specific  inhibitor  of  EZH2  methyltransferase,  decreases  the  level  ofH3K27Me3, the product of EZH2's enzymatic activity. However, GSK343 exhibited limited effectson the growth of EOC cells in conventional two-dimensional (2D) culture. In contrast, GSK343significantly suppressed the growth of EOC cells cultured in 3D matrigel extracellular matrix(ECM),  which  more  closely  mimics  the  tumor  microenvironment  in  vivo.  Notably,  GSK343induces apoptosis of  EOC cells  in 3D but not 2D culture.  In addition,  GSK343 significantlyinhibited the invasion of EOC cells. In summary, we show that the 3D ECM sensitizes EOC cellsto EZH2 methyltransferase inhibition,  which suppresses cell  growth,  induces apoptosis  andinhibits  invasion.  Our  findings  imply  that  in  EZH2 wild-type  solid  tumors,  the  ECM tumormicroenvironment plays an important role in determining sensitivity to EZH2 inhibition andsuggest  that  targeting  the  ECM represents  a  novel  strategy  for  enhancing  EZH2 inhibitorefficacy. © 2013 Landes Bioscience.http://dx.doi.org/10.4161/cc.25163Keywords3D culture, Apoptosis, Epithelial ovarian cancer, EZH2, EZH2 inhibitor GSK343

http://dspace.kpfu.ru/xmlui/bitstream/net/139339/-1/SCOPUS15384101-2013-12-13-SID84879773777-a1.pdf

La Patrie : journal quotidien, politique, commercial et littéraire

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Gallica, Bibliotheque Numerique

Kazan Federal University Digital Repository

Kazan Federal University Digital Repository