Loss of DRD5P2 in hypoxia attenuates Rock2 degradation to promote EMT and gastric cancer metastasis.

Background: Metastasis is the leading cause of gastric cancer (GC)-related death. However, the molecular mechanisms underlying GC metastasis are not well understood. In this study, we focused on dopamine receptor 5 pseudogene 2 (DRD5P2), a novel long non-coding RNA, in GC metastasis.

Methods: Expression of DRD5P2 in GC was detected by real-time PCR (RT-PCR) and fluorescence in situ hybridization (FISH). The effect of DRD5P2 in GC cells was examined by transwell invasion and migration assays. The pathways underlying DRD5P2/Rock2 signaling were studied by Western blot, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) analysis. Regulatory mechanism between hypoxia and DRD5P2 expression was explored in vitro by ChIP and Dual-luciferase reporter assays.

Results: DRD5P2 expression is downregulated in advanced human GC and is associated with poor clinical outcomes. Gain- and loss-of-function studies showed that DRD5P2 inhibits GC cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, as well as peritoneal dissemination in vivo. Mechanistic analysis revealed that DRD5P2 binds with Rock2 and recruits the E3 ubiquitin ligase KAP1 to mediate Rock2 degradation, thus suppressing the Ezrin/HRAS/ERK/CREB pathway and ultimately attenuating Snail-mediated EMT and GC metastasis. Furthermore, DRD5P2 transcription is inhibited by hypoxia in a HIF-1α/ZNF263-dependent manner in GC cells.

Conclusions: DRD5P2 acts as a tumor suppressor in GC metastasis by suppressing Rock2/ERK/Snail signaling, and DRD5P2 is transcriptionally suppressed under hypoxia via the HIF-1α/ZNF263 axis.