Oncostatin M induces epigenetic reprogramming in renal cell carcinoma-associated endothelial cells
Clear-cell renal cell carcinoma (ccRCC) is the most prevalent and lethal subtype of renal cell carcinoma. Genomic and epigenomic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a crucial early event in ccRCC pathogenesis (~75% of cases). Loss of VHL function leads to dysregulated hypoxia signaling, resulting in an extensive, disorganized, tortuous, and leaky vascular network within ccRCC tissue. It has been shown previously that Oncostatin M (OSM) secreted by the VHL-deficient kidney tubule cells can induce most of these ccRCC-associated vascular phenotypes which in turn promote tumor cell proliferation, immune cell infiltration, and metastasis. The influence of OSM to ECs could induce extensive and long-lasting transcriptomic changes in ECs although these ECs did not harbor any genomic mutations. The observations suggest a novel interaction mechanism between tumor cells and stromal cells, in which OSM emanating from the tumor cells may induce transcriptomic changes in ECs via epigenetic modification. To further explore the underlying mechanisms, we directly treated HMEC-1, a microvascular endothelial cell, with recombination OSM with or without histone acetylation inhibitors. The total mRNA of these samples was then performed mRNA Sequencing (mRNA-Seq). Overall design: 4x10^4 HMEC-1 cells were seeded in 3.5 cm2 culture dish and grown overnight. The media was replaced with fresh complete media (Control; CT group), 10 ng/mL of rOSM (OSM group), 30 ?g/mL PF9363 + 10 ng/mL of rOSM (PF9363 group) or 10 ?g/mL CBP300 + 10 ng/mL of rOSM (CBP300 group). The total mRNA was harvested after 48 hr for mRNA-Seq.