PKCepsilon is essential for gelsolin expression by histone deacetylase inhibitor apicidin in human cervix cancer cells.
Down-regulation of gelsolin expression is associated with cellular transformation and induction of gelsolin exerts antitumorigenic effects. In this study, we show that protein kinase C (PKC) signaling pathway is required for the induction of gelsolin by the histone deacetylase inhibitor apicidin in HeLa cells. Apicidin induces gelsolin mRNA independently of the de novo protein synthesis. Inhibitor study has revealed that the PKC signaling pathway is involved in the gelsolin expression. Furthermore, inhibition of PKCepsilon by either siRNA or dominant-negative mutant completely abrogates the expression of gelsolin by apicidin, indicating that PKCepsilon is the major isoform for this process. In parallel, apicidin induction of gelsolin is antagonized by the inhibition of Sp1 using dominant-negative Sp1 or specific Sp1 inhibitor mithramycin, and inhibition of PKC leads to suppression of Sp1 promoter activity. Our results provide mechanistic insights into molecular mechanisms of gelsolin induction by apicidin.
Eun
Dae-Wook
DW
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Ahn
Seong Hoon
SH
You
Jeong Soo
JS
Park
Jong Woo
JW
Lee
Eun Kyung
EK
Lee
Hyun Nah
HN
Kang
Gil Myoung
GM
Lee
Jae Cheol
JC
Choi
Wahn Soo
WS
Seo
Dong-Wan
DW
Han
Jeung-Whan
JW
D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018260:Gelsolin / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009154:Mutation; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
D004791:Enzyme Inhibitors; D018260:Gelsolin; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C102351:apicidin; D051744:Protein Kinase C-epsilon