HOTAIR Promotes the Hyperactivation of PI3K/Akt and Wnt/β-Catenin Signaling Pathways via PTEN Hypermethylation in Cervical Cancer

The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/beta-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression-either by knockdown or overexpression-significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/beta-catenin pathways. Additionally, we discovered that HIF1 alpha directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1 alpha in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/beta-catenin pathways through the HOTAIR/HIF1 alpha axis, thereby contributing to the oncogenic phenotype of cervical cancer.