The aspirin-induced long non-coding RNA OLA1P2 blocks phosphorylated STAT3 homodimer formation

Abstract

BackgroundAlthough the chemopreventive effects of aspirin have been extensively investigated, the roles of many cell components, such as long non-coding RNAs, in these effects are still not completely understood.ResultsWe identify an aspirin-induced upregulated lncRNA, OLA1P2, in human colorectal cancer. Aspirin induces demethylation of the FOXD3 promoter and promotes expression of the FOXD3 gene. Subsequently, upregulated FOXD3 protein transcriptionally activates lncRNA OLA1P2 expression. OLA1P2 upregulation markedly affects STAT3 signaling pathway activity by inhibiting the nuclear import of phosphorylated STAT3. The phosphorylation of tyrosine-705 of STAT3 is the first step in OLA1P2 binding, and the formation of phosphorylated STAT3 homodimers is subsequently blocked. OLA1P2 interacts directly with STAT3 due to OLA1P2 sharing the same conservative STAT3 transcription response element as STAT3 targets. Regular use of aspirin dramatically decreases the number of metastatic nodules of cancer cells in immunodeficient mouse lungs, and OLA1P2 silencing markedly weakens the anti-metastatic activity of aspirin in the lungs. Additionally, low OLA1P2 levels are associated with malignant transformation and lower overall survival in cancers.ConclusionsThe present study finds that the aspirin-FOXD3-OLA1P2-STAT3 axis exhibits exciting anticancer effects and provides new insights into the chemopreventive mechanisms underlying aspirin use.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0892-5) contains supplementary material, which is available to authorized users.

Long noncoding RNA TSLNC8 is a tumor suppressor that inactivates the interleukin‐6/STAT3 signaling pathway

“…The lnc‐DC binds directly to STAT3 and promotes STAT3 phosphorylation at Y705 by preventing STAT3 from binding to phosphatase small heterodimer partner 1 . OLA1P2 binds to STAT3, inhibits the phosphorylation of Y705, and blocks phosphorylated STAT3 homodimer formation . Here, we showed that TSLNC8 binds to the DNA‐binding domain of STAT3 but not the C‐terminal domain containing the Y705 and S727 sites, which binds with lnc‐DC or OLA1P2, and that the STAT3 recognized site at the 748‐758 nucleotides of TSLNC8 is important for the biological function of this lncRNA.…”

“…As a promising molecular target for the treatment of various cancers, STAT3 is activated in many cancer types . Several lncRNAs regulate the phosphorylation status of STAT3 and alter its nuclear import–export dynamics . The lnc‐DC binds directly to STAT3 and promotes STAT3 phosphorylation at Y705 by preventing STAT3 from binding to phosphatase small heterodimer partner 1 .…”

Overexpression of the long noncoding RNA TRHDE‐AS1 inhibits the progression of lung cancer via the miRNA‐103/KLF4 axis

“…1 More than 50% of patients with lung cancer are diagnosed with a very poor prognosis, and approximately 30% of the patients do not get adequate treatment. [2][3][4] Lung cancer has become a life-threatening disease and seriously influences people's quality of life. Researchers have spared no efforts to determine the mechanism of lung cancer and to accelerate the clinical treatment.…”

Complex roles of the old drug aspirin in cancer chemoprevention and therapy

“…The list of aspirin targets keeps increasing. Aspirin reportedly acetylates P53 and histone, and induces FoxD3 promoter demethylation and FoxD3 expression thereby inducing lncRNA OLA1P2, which inhibits the nuclear import of phosphorylated STAT3 . Moreover, aspirin inhibits NF‐κB signaling thereby relieving acquired drug resistance in breast cancer .…”