Activation of OSM-STAT3 Epigenetically Regulates Tumor-Promoting Transcriptional Programs in Cervical Cancer

SIMPLE SUMMARY: Oncostatin M (OSM) induces Signal Transducer and Transcription 3 (STAT3) activation, exacerbating cervical cancer. The molecular mechanism by which the OSM-STAT3 axis regulates tumor-progression-related genes in cervical cancer is not well understood. Our transcriptomic and epigenomic analysis showed that OSM-induced hypoxia, wound healing, and angiogenesis genes were significantly inhibited by SD-36, the STAT3-selective degrader. Open chromatin regions of the genes that were OSM-STAT3-regulated were consistently enriched for STAT3 binding motifs. Higher levels of OSM-regulated genes’ expression were significantly linked to a poor prognosis in patients with cervical cancer. These findings show that the OSM-STAT3 signaling pathway regulates important transcriptomic programs via epigenetic modifications and that selective STAT3 inhibition may represent a novel therapeutic approach for patients with advanced cervical cancer. ABSTRACT: Despite improvements in preventative strategies, such as regular screenings with Pap tests and human papillomavirus (HPV) tests as well as HPV vaccinations, effective treatment for advanced cervical cancer remains poor. Deregulation of STAT3 is an oncogenic factor that promotes tumorigenesis and epithelial-to-mesenchymal transition (EMT) in various cancers. Oncostatin M (OSM), a pleiotropic cytokine, induces STAT3 activation, exacerbating cervical cancer. However, the mechanism by which the OSM-STAT3 axis epigenetically regulates tumor-progression-related genes in cervical cancer is not well understood. Here, we show that OSM-mediated STAT3 activation promotes pro-tumorigenic gene expression programs, with chromatin remodeling in cervical cancer. Reanalysis of scRNA-seq data performed in cervical cancer uncovered an interaction between the oncostatin M receptor (OSMR) on tumor cells and OSM induced by tumor-associated macrophages (TAMs). Our gene expression profiling (bulk RNA-seq) shows that OSM-induced genes were involved in hypoxia, wound healing, and angiogenesis, which were significantly inhibited by SD-36, a STAT3-selective degrader. Additionally, ATAC-seq experiments revealed that STAT3 binding motifs were preferentially enriched in open chromatin regions of the OSM-STAT3-regulated genes. Among the 50 candidate genes that were regulated epigenetically through the OSM-STAT3 axis, we found that the expression levels of NDRG1, HK2, PLOD2, and NPC1 were significantly correlated with those of OSMR and STAT3 in three independent cervical cancer cohorts. Also, higher expression levels of these genes are significantly associated with poor prognosis in cervical cancer patients. Collectively, our findings demonstrate that the OSM-STAT3 signaling pathway regulates crucial transcriptomic programs through epigenetic changes and that selective inhibition of STAT3 may be a novel therapeutic strategy for patients with advanced cervical cancer.