PLCε regulates metabolism and metastasis signaling via HIF-1α/MEK/ERK pathway in prostate cancer

Phospholipase C-epsilon (PLC epsilon) is frequently overexpressed in tumors and plays an important role in the regulation of tumorigenesis. Although great progress has been made in understanding biological roles of PLC epsilon, the relevant molecular mechanisms underlying its pro-tumor activity remain largely unclear. Here, we demonstrated that PLC epsilon knockdown reduced cell metastasis, glucose consumption and lactate production in a manner that depended on hypoxia inducible factor 1 alpha (HIF-1 alpha) expression in prostate cancer cells. Interestingly, our findings showed that the expression levels of PLC epsilon were positively associated with those of HIF-1 alpha in clinical prostate carcinoma samples. Knockdown of PLC epsilon impaired HIF-1 alpha levels and transcriptional activity by regulating the extracellular-signal-regulated kinase pathway, and blocking HIF-1 alpha nuclear translocation. Furthermore, PLC epsilon could interact with the von Hippel-Lindau E3 ligase complex to modulate the stability of HIF-1 alpha. Collectively, our findings demonstrate that PLC epsilon could be a crucial positive regulator of HIF-1 alpha, which would promote PLC epsilon-enhanced tumorigenesis.