TY - JOUR
T1 - Acetylation-dependent regulation of essential iPS-inducing factors
T2 - A regulatory crossroad for pluripotency and tumorigenesis
AU - Dai, Xiangpeng
AU - Liu, Pengda
AU - Lau, Alan W.
AU - Liu, Yueyong
AU - Inuzuka, Hiroyuki
N1 - Publisher Copyright:
© 2014 The Authors.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Induced pluripotent stem (iPS) cells can be generated from somatic cells by coexpression of four transcription factors: Sox2, Oct4, Klf4, and c-Myc. However, the low efficiency in generating iPS cells and the tendency of tumorigenesis hinder the therapeutic applications for iPS cells in treatment of human diseases. To this end, it remains largely unknown how the iPS process is subjected to regulation by upstream signaling pathway(s). Here, we report that Akt regulates the iPS process by modulating posttranslational modifications of these iPS factors in both direct and indirect manners. Specifically, Akt directly phosphorylates Oct4 to modulate the Oct4/Sox2 heterodimer formation. Furthermore, Akt either facilitates the p300-mediated acetylation of Oct4, Sox2, and Klf4, or stabilizes Klf4 by inactivating GSK3, thus indirectly modulating stemness. As tumorigenesis shares possible common features and mechanisms with iPS, our study suggests that Akt inhibition might serve as a cancer therapeutic approach to target cancer stem cells. Akt regulates the induced pluripotent stem (iPS) process by modulating posttranslational modifications of iPS factors in both direct and indirect manners. Specifically, Akt directly phosphorylates Oct4 to modulate the Oct4/Sox2 heterodimer formation. Furthermore, Akt either facilitates the p300-mediated acetylation of Oct4, Sox2, and Klf4, or stabilizes Klf4 by inactivating GSK3, to indirectly modulate stemness.
AB - Induced pluripotent stem (iPS) cells can be generated from somatic cells by coexpression of four transcription factors: Sox2, Oct4, Klf4, and c-Myc. However, the low efficiency in generating iPS cells and the tendency of tumorigenesis hinder the therapeutic applications for iPS cells in treatment of human diseases. To this end, it remains largely unknown how the iPS process is subjected to regulation by upstream signaling pathway(s). Here, we report that Akt regulates the iPS process by modulating posttranslational modifications of these iPS factors in both direct and indirect manners. Specifically, Akt directly phosphorylates Oct4 to modulate the Oct4/Sox2 heterodimer formation. Furthermore, Akt either facilitates the p300-mediated acetylation of Oct4, Sox2, and Klf4, or stabilizes Klf4 by inactivating GSK3, thus indirectly modulating stemness. As tumorigenesis shares possible common features and mechanisms with iPS, our study suggests that Akt inhibition might serve as a cancer therapeutic approach to target cancer stem cells. Akt regulates the induced pluripotent stem (iPS) process by modulating posttranslational modifications of iPS factors in both direct and indirect manners. Specifically, Akt directly phosphorylates Oct4 to modulate the Oct4/Sox2 heterodimer formation. Furthermore, Akt either facilitates the p300-mediated acetylation of Oct4, Sox2, and Klf4, or stabilizes Klf4 by inactivating GSK3, to indirectly modulate stemness.
KW - Akt
KW - Klf4
KW - Oct4
KW - P300
KW - Sox2
KW - iPS cell
UR - http://www.scopus.com/inward/record.url?scp=84991454133&partnerID=8YFLogxK
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U2 - 10.1002/cam4.298
DO - 10.1002/cam4.298
M3 - Article
C2 - 25116380
AN - SCOPUS:84991454133
VL - 3
SP - 1211
EP - 1224
JO - Cancer Medicine
JF - Cancer Medicine
SN - 2045-7634
IS - 5
ER -