Dihydrotanshinone I suppresses ovarian cancer by targeting splicing factor SRSF1 to regulate the long non-coding RNA SLC8A1-AS1/FOXO1 axis.
TL;DR
This study identifies SLC8A1-AS1 as a novel prognostic biomarker in OC and provides the first evidence that DHT exerts its antitumor effects by targeting the SRSF1/SLC8A1-AS1/FOXO1 axis.
Abstract
Background
Ovarian cancer (OC) is a lethal malignancy with limited therapies. The natural compound dihydrotanshinone I (DHT) exhibits broad antitumor activity, yet its precise molecular targets and mechanistic interplay with oncogenic lncRNAs in OC remain largely unexplored.
Purpose
This study aimed to investigate the molecular targets and underlying mechanisms of DHT‑regulated lncRNAs in OC. STUDY
Design
DHT efficacy was evaluated in vitro and in vivo. Mechanisms were investigated via lncRNA profiling, transcriptomic analysis, functional assays, and protein‑binding experiments.
Methods
The antitumor efficacy of DHT was assessed in OC cells and xenograft models. LncRNA candidates were screened using microarray and validated by clinical cohort analysis. The regulatory role of SLC8A1-AS1 was further verified through functional assays. RNA pull-down/MS and RIP were performed to identify proteins binding to SLC8A1-AS1. Rescue experiments were conducted to evaluate whether SRSF1 influences SLC8A1-AS1 stability. The DHT-SRSF1 interaction and binding sites were examined through SPR, CETSA, DARTS, MS, and molecular docking. Transcriptomics and western blot were conducted to analyze downstream signaling cascades.
Results
DHT significantly suppressed OC growth. SLC8A1-AS1 was highly expressed and associated with poor prognosis in OC. Mechanistically, SRSF1 bound to SLC8A1-AS1 and enhanced its stability, activating the PI3K/AKT/FOXO1 pathway. DHT directly bound to SRSF1 and induced its degradation, downregulating SLC8A1-AS1 expression and inactivating the pathway, ultimately suppressing proliferation in OC.
Conclusions
This study identifies SLC8A1-AS1 as a novel prognostic biomarker in OC and provides the first evidence that DHT exerts its antitumor effects by targeting the SRSF1/SLC8A1-AS1/FOXO1 axis. These findings unveil the role of SLC8A1-AS1 in OC progression and elucidate the mechanistic basis for the therapeutic potential of DHT.