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

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

Research output: Contribution to journalArticlepeer-review

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
Article number35480
Number of pages11
JournalScientific Reports
Volume6
Early online date21 Oct 2016
DOIs
Publication statusPublished - 21 Oct 2016

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