FBXO11 represses cellular response to hypoxia by destabilizing hypoxia-inducible factor-1α mRNA

The transcriptional factor hypoxia-inducible factor-1α (HIF-1α) is induced under hypoxia and plays crucial roles in cancer progression and angiogenesis. Protein arginine methyltransferases (PRMTs), 11 isoforms of which have been identified so far, modulates the functions of diverse proteins by catalyzing arginine methylation in post-translational level. PRMT9 (alternatively named FBXO11) and PRMT11 (FBXO10) are expected to have the E3 ubiquitin ligase activity through their F-box domains as well as the methyltrasferase activity. Given previous studies examining roles of 8 PRMT isoforms (PRMT1-8) in the HIF-1 signaling pathway, PRMT1 and PRMT5 were demonstrated to regulate HIF-1α expression in opposite ways. We herein examined if FBXO10 and FBXO11 participate in the HIF-1 signaling pathway. Consequently, the siRNA-mediated knockdown of FBXO11 facilitated HIF-1α expression in various cancer cells and HIF-1-driven gene expressions, but the FBXO10 knockdown did not. Mechanistically, FBXO11 was found to inhibit de novo synthesis of HIF-1α protein by destabilizing HIF-1α mRNA. Since a FBXO11 mutant lacking F-box failed to reverse the HIF-1α expression by FBXO11 knockdown, the FBXO11 regulation of HIF-1α may be attributed to the ubiquitination of some proteins controlling HIF-1α mRNA stability. Considering the oncogenic roles of HIF-1α, FBXO11 is suggested to act as a tumor suppressor and also to be a potential target for cancer therapy.