Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124

Peixin Dong, Ying Xiong, Hidemichi Watari, Sharon Jb Hanley, Yosuke Konno, Kei Ihira, Fumihiko Suzuki, Takahiro Yamada, Masataka Kudo, Junming Yue, Noriaki Sakuragi

Research output: Contribution to journalArticle

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Abstract

Derepression of wild-type p53 by suppressing its negative inhibitor iASPP (Inhibitor of apoptosis-stimulating protein of p53) represents a potential therapeutic option for cervical cancer (CC). Here, we reported a novel functional significance of iASPP upregulation in cervical tumorigenesis: iASPP acts as a key promoter of CC cell proliferation, epithelial-mesenchymal transition, invasion and cancer stemness, by interacting with p53 to suppress p53-mediated transcription of target genes and reducing p53-responsive microRNA-34a levels. Moreover, we demonstrate that miR-124, directly targeting iASPP, reduces expression of iASPP and attenuates CC cell growth and invasiveness. Low miR-124 expression is inversely correlated with increased expression of iASPP mRNA in CC tissues. In a cohort of 40 patients with CC, the low miR-124 expression was correlated with poor 5-year overall survival (P = 0.0002) and shorter disease-free survival 5-year (P = 0006). Treatment with the DNA methyltransferase inhibitor Zebularine increases miR-124 expression and retards CC cell growth and invasion with minimal toxicity to normal cells. Even at a non-toxic concentration, Zebularine was effective in suppressing CC cell invasion and migration. Altogether, the restoration of miR-124 reduces iASPP expression and leads to p53-dependent tumor suppression, suggesting a therapeutic strategy to treat iASPP-associated CC.

Original languageEnglish (US)
Article number35480
JournalScientific reports
Volume6
DOIs
StatePublished - Oct 21 2016

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Inhibitor of Apoptosis Proteins
MicroRNAs
Uterine Cervical Neoplasms
Methylation
pyrimidin-2-one beta-ribofuranoside
Epithelial-Mesenchymal Transition
p53 Genes
Methyltransferases
Growth
Disease-Free Survival
Cell Movement
Neoplasms
Carcinogenesis
Up-Regulation
Therapeutics
Cell Proliferation
Messenger RNA
Survival
DNA

All Science Journal Classification (ASJC) codes

  • General

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Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124. / Dong, Peixin; Xiong, Ying; Watari, Hidemichi; Hanley, Sharon Jb; Konno, Yosuke; Ihira, Kei; Suzuki, Fumihiko; Yamada, Takahiro; Kudo, Masataka; Yue, Junming; Sakuragi, Noriaki.

In: Scientific reports, Vol. 6, 35480, 21.10.2016.

Research output: Contribution to journalArticle

Dong, P, Xiong, Y, Watari, H, Hanley, SJ, Konno, Y, Ihira, K, Suzuki, F, Yamada, T, Kudo, M, Yue, J & Sakuragi, N 2016, 'Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124', Scientific reports, vol. 6, 35480. https://doi.org/10.1038/srep35480
Dong, Peixin ; Xiong, Ying ; Watari, Hidemichi ; Hanley, Sharon Jb ; Konno, Yosuke ; Ihira, Kei ; Suzuki, Fumihiko ; Yamada, Takahiro ; Kudo, Masataka ; Yue, Junming ; Sakuragi, Noriaki. / Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124. In: Scientific reports. 2016 ; Vol. 6.
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