RORγ hijacks HIF-1α to promote peritoneal metastasis of gastric cancer

Peritoneal metastasis (PM) is diagnosed in almost half of patients with advanced gastric cancer (GCa) and has a very poor prognosis. However, the molecular mechanisms of PM in GCa remain poorly understood. Here, we show that the elevated expression of RAR-related orphan receptor gamma (RORγ) in GCa tumors is a key driver of PM. RORγ drives GCa progression and metastasis by assembling a transcriptional complex with HIF-1α that regulates the expression of HIF-1α targets via recruitment of RNA polymerase II and p300. Mechanistically, RORγ hijacks HIF-1α to disrupt the interaction between HIF-1α and PHD3, leading to decreased HIF-1α hydroxylation, ubiquitylation and increased HIF-1α accumulation, nuclear translocation, and transactivation. RORγ antagonists block tumor growth and PM in multiple xenograft GCa models, and they effectively sensitize GCa tumors to chemotherapy in mice. Thus, our study uncovers a mechanism of RORγ-driven PM and offers a potential therapeutic option against advanced GCa. A total of 7 samples were analyzed in this study. The study included three gastric cancer cell lines MKN45, AGS and HGC27. MKN45 cells were cultured in a normoxic incubator for 24 h or in a hypoxic incubator with certified gas containning 94% N2, 1%O2 and 5%CO2 for 24 h. AGS cells were cultured in growth medium containing Vehicel control (DMSO) or GSK805 (5 μM) for 48 h. For HGC27, cells transfected with Vector plasmid (HGC27-Vector) and RORγ overexpressing HGC27 stable transfectants (HGC27-RORC) were cultured in growth medium. After treadment, all cells were collected for RNA-seq assay.