Molecular and Cellular Pathobiology Human Rhomboid Family-1 Suppresses Oxygen-Independent Degradation of Hypoxia-Inducible Factor-1a in Breast Cancer

Intermittent oxygen deficiency in cancers promotes prolonged inflammation, continuous angiogenesis, and increased drug resistance. Hypoxia-inducible factor-1 (HIF1) has a pivotal role in the regulation of cellular responses to oxygen deficiency. The a-subunit of HIF1 (HIF1a) is degraded in normoxia but stabilized in hypoxia. However, the molecular mechanism that controls oxygen-independent degradation of HIF1a has remained elusive. Human rhomboid family-1 (RHBDF1) is a member of a large family of nonprotease rhomboids whose function is basically unknown. We report here that RHBDF1 expression in breast cancer is highly elevated and is strongly correlated with escalated disease progression, metastasis, poor prognosis, and poor response to chemotherapy. We show that RHBDF1 interaction with the receptor of activated protein-C kinase-1 (RACK1) in breast cancer cells prevents RACK1-assisted, oxygen-independent HIF1a degradation. In addition, we show that the HIF1a-stabilizing activity of RHBDF1 diminishes when the phosphorylation of a tyrosine residue on the RHBDF1 molecule is inhibited. These findings are consistent with the view that RHBDF1 is a critical component of a molecular switch that regulates HIF1a stability in cancer cells in hypoxia and that RHBDF1 is of potential value as a new target for cancer treatment. Cancer Res; 74(10); 1–12. 2014 AACR.