Hypoxia drives CBR4 down-regulation promotes gastroenteropancreatic neuroendocrine tumors via activation mammalian target of rapamycin mediated by fatty acid synthase

Abstract

Hypoxia has been highly proven a hallmark of tumor micro-environment, promoting the malignant phenotypes, playing a crucial role from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Increasing evidence also showed that hypoxia mediated the abnormal lipid metabolism in cancer by regulating various oncogenic signal pathways. However, it is still unclear but attractive how hypoxia specifically functioned and changed the condition of the tumor micro-environment. In present study, we find that hypoxia promoted the methylation degree of CBR4 promoter region thus downgraded the expression of CBR4, which promoted GEP-NETs progression and increased the sensitivity of GEP-NETs cells to everolimus. Further, CBR4 interacted with fatty acid synthase (FASN), displaying a down-regulation of FASN by activating the ubiquitin proteasome pathway and suppressed mTOR signaling. Overall, our results uncovers the CBR4/FASN/mTOR axis as a mechanism for tumor development and inspires us a new molecular guide for the therapeutic strategies for GEP-NETs treatment.