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

Junho Noh; Chaelin You; Keunsoo Kang; Kyuho Kang

doi:10.3390/cancers14246090

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

Cancers (Basel). 2022 Dec 10;14(24):6090. doi: 10.3390/cancers14246090.

Authors

Junho Noh¹, Chaelin You¹, Keunsoo Kang², Kyuho Kang¹

Affiliations

¹ Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju 28644, Republic of Korea.
² Department of Microbiology, College of Science & Technology, Dankook University, Cheonan 31116, Republic of Korea.

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.

Keywords: Oncostatin M; STAT3; cervical cancer; chromatin remodeling; epigenome; transcriptome.

Grants and funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1C1C1013939 and NRF-2020R1A6A1A03043283).