BACKGROUND: The PI3K pathway controls diverse cellular processes including growth, survival, metabolism, and apoptosis. Nuclear FOXO factors were observed in cancers that harbor constitutively active PI3K pathway output and stem signatures. FOXO1 and FOXO3 were previously published to induce stem genes such as OCT4 in embryonic stem cells. Here, we investigated FOXO-driven stem gene expression in U87MG glioblastoma cells. METHODS: PI3K-activated cancer cell lines were investigated for changes in gene expression, signal transduction, and clonogenicity under conditions with FOXO3 disruption or exogenous expression. The impact of PI3K pathway inhibition on stem gene expression was examined in a set of glioblastoma cell lines. RESULTS: We found that CRISPR-Cas9-mediated FOXO3 disruption in U87MG cells caused decreased OCT4 and SOX2 gene expression, STAT3 phosphorylation on tyrosine 705 and clonogenicity. FOXO3 over expression led to increased OCT4 in numerous glioblastoma cancer cell lines. Strikingly, treatment of glioblastoma cells with NVP-BEZ235 (a dual inhibitor of PI3K and mTOR), which activates FOXO factors, led to robust increases OCT4 gene expression. Direct FOXO factor recruitment to the OCT4 promoter was detected by chromatin immunoprecipitation analyses using U87MG extracts. DISCUSSION: We show for the first time that FOXO transcription factors promote stem gene expression glioblastoma cells. Treatment with PI3K inhibitor NVP-BEZ235 led to dramatic increases in stem genes in a set of glioblastoma cell lines. CONCLUSION: Given that, PI3K inhibitors are actively investigated as targeted cancer therapies, the FOXO-mediated induction of stem genes observed in this study highlights a potential hazard to PI3K inhibition. Understanding the molecular underpinnings of stem signatures in cancer will allow refinements to therapeutic strategies. Targeting FOXO factors to reduce stem cell characteristics in concert with PI3K inhibition may prove therapeutically efficacious.
BACKGROUND: The PI3K pathway controls diverse cellular processes including growth, survival, metabolism, and apoptosis. Nuclear FOXO factors were observed in cancers that harbor constitutively active PI3K pathway output and stem signatures. FOXO1 and FOXO3 were previously published to induce stem genes such as OCT4 in embryonic stem cells. Here, we investigated FOXO-driven stem gene expression in U87MGglioblastoma cells. METHODS: PI3K-activated cancer cell lines were investigated for changes in gene expression, signal transduction, and clonogenicity under conditions with FOXO3 disruption or exogenous expression. The impact of PI3K pathway inhibition on stem gene expression was examined in a set of glioblastoma cell lines. RESULTS: We found that CRISPR-Cas9-mediated FOXO3 disruption in U87MG cells caused decreased OCT4 and SOX2 gene expression, STAT3 phosphorylation on tyrosine 705 and clonogenicity. FOXO3 over expression led to increased OCT4 in numerous glioblastoma cancer cell lines. Strikingly, treatment of glioblastoma cells with NVP-BEZ235 (a dual inhibitor of PI3K and mTOR), which activates FOXO factors, led to robust increases OCT4 gene expression. Direct FOXO factor recruitment to the OCT4 promoter was detected by chromatin immunoprecipitation analyses using U87MG extracts. DISCUSSION: We show for the first time that FOXO transcription factors promote stem gene expression glioblastoma cells. Treatment with PI3K inhibitor NVP-BEZ235 led to dramatic increases in stem genes in a set of glioblastoma cell lines. CONCLUSION: Given that, PI3K inhibitors are actively investigated as targeted cancer therapies, the FOXO-mediated induction of stem genes observed in this study highlights a potential hazard to PI3K inhibition. Understanding the molecular underpinnings of stem signatures in cancer will allow refinements to therapeutic strategies. Targeting FOXO factors to reduce stem cell characteristics in concert with PI3K inhibition may prove therapeutically efficacious.
Authors: Ji-Hye Paik; Ramya Kollipara; Gerald Chu; Hongkai Ji; Yonghong Xiao; Zhihu Ding; Lili Miao; Zuzana Tothova; James W Horner; Daniel R Carrasco; Shan Jiang; D Gary Gilliland; Lynda Chin; Wing H Wong; Diego H Castrillon; Ronald A DePinho Journal: Cell Date: 2007-01-26 Impact factor: 41.582
Authors: Yuin-Han Loh; Qiang Wu; Joon-Lin Chew; Vinsensius B Vega; Weiwei Zhang; Xi Chen; Guillaume Bourque; Joshy George; Bernard Leong; Jun Liu; Kee-Yew Wong; Ken W Sung; Charlie W H Lee; Xiao-Dong Zhao; Kuo-Ping Chiu; Leonard Lipovich; Vladimir A Kuznetsov; Paul Robson; Lawrence W Stanton; Chia-Lin Wei; Yijun Ruan; Bing Lim; Huck-Hui Ng Journal: Nat Genet Date: 2006-03-05 Impact factor: 38.330
Authors: Judith Hagenbuchner; Martina Rupp; Christina Salvador; Bernhard Meister; Ursula Kiechl-Kohlendorfer; Thomas Müller; Kathrin Geiger; Consolato Sergi; Petra Obexer; Michael J Ausserlechner Journal: Oncotarget Date: 2016-11-22
Authors: Neftali Vazquez; Alma Lopez; Victoria Cuello; Michael Persans; Erin Schuenzel; Wendy Innis-Whitehouse; Megan Keniry Journal: Cancer Treat Res Commun Date: 2021-02-17